MXPA06007364A - Nucleic acid encoding a novel prostaglandin receptor protein and methods of use thereof - Google Patents

Abstract

Described herein is a novel member of the prostanoid receptor family, a guinea pig prostaglandin D2 receptor. Described are the receptor, the nucleic acid that encodes it, and various uses for both.

Description

NUCLEIC ACID CODIFIES A NEW DP RECEPTOR PROTEIN AND METHODS OF USE OF THE SAME FIELD OF THE INVENTION The present invention relates generally to a nucleic acid molecule encoding a hitherto unknown member of the family of prostanoid receptors. BACKGROUND OF THE INVENTION Prostanoids, including prostaglandin (PG), prostacyclin and thromboxane (TX), are important mediators of central and peripheral physiological effects. Prostaglandin D2 (PGD2) is formed in a variety of tissues including brain, spleen, lung, bone marrow, stomach, skin and also in mast cells (Lewis et al., 1982). PGD2 has been implicated in many physiological events in both the central nervous system and peripheral tissues. In the central nervous system, it has been shown that PGD2 affects the induction of sleep, body temperature, olfactory function, hormone release and nociception. Peripherally, PGD2 is the main product of cyclooxygenase of arachidonic acid produced by mast cells after immunological confrontation. It has been shown that confronting local allergens in patients with allergic rhinitis, bronchial asthma, allergic conjunctivitis and atopic dermatitis results in a rapid increase in PGD2 levels in nasal and bronchial lavage fluids, tears and fluids of the skin cameras. Activated mast cells, a major source of PGD2, are one of the key factors in stimulating the allergic response in conditions such as asthma, allergic rhinitis, allergic conjunctivitis, allergic dermatitis and other diseases (Brightling et al., 2003) . Analogously, PGD2 has many inflammatory actions, such as increased vascular permeability in the conjunctiva and skin, increased skin and skin, increased nasal airway resistance, narrowing of the airways and infiltration of eosinophils in the conjunctiva and the trachea. For this reason, it is considered that PGD2 is one of the key factors in the stimulation of inflammatory reactions. Initial efforts have focused on the identification of distinct receptors for the five naturally occurring bioactive prostanoids, PGD2, PGE2 / PGF2a / PGI2 and TXA2, resulting in the classification of 5 basic types of prostanoid receptors: DP, EP, FP receptors. , prostacyclin (IP) and thromboxane (TP), respectively (Coleman et al., 1994). Many of the actions of prostaglandin D2 are mediated by its action on the type D prostaglandin (DP) receptor, a G-protein coupled receptor. Although it was originally believed that each prostanoid acted preferentially on individual receptors, the researchers They study the biology of prostanoids have begun to appreciate the promiscuity of these ligands to interact with members of different families of receptors. Thus, it is becoming increasingly clear that in order to understand signaling by prostanoids it is necessary to elucidate the biological consequences of the activation of prostanoid receptors. The DP receptor is particularly interesting because it is found in both central cells and peripheral cells, suggesting its involvement in the mediation of diverse biological pathways and, consequently, its potential therapeutic importance in many disease states. DP receptors have been identified in the brain, and PGD2 produces effects on sleep induction, body temperature, olfactory function, and hormone release (Negishi et al., 1993; Wright et al., 1999 and references cited in said places). DP receptors have also been located in discrete and distinct populations of the spinal cord. This observation may explain the discordant effects of hyperalgesia and allodynia (discomfort by innocuous tactile stimuli) induced by PGD2- DP receptors are also present in the gastrointestinal tract and have been implicated in the contractile response of the Gl tract (Wright et al., 1999; Ito et al., 1989). Additionally, it has been demonstrated that DP receptor ligands induce mucus secretion and intestinal cell proliferation. Glycogenesis in the liver can also be regulated by DP receptors (Ito et al., 1989). DP receptors are found in the eye, and agonists reduce intraocular pressure, suggesting a role in glaucoma. Platelets contain the DP receptor and PGD2 has been shown to inhibit platelet aggregation, which supports a role for the DP receptor in the modulation of blood disorders such as thrombosis (Armstrong, 1996). Thus, the varied expression of the DP receptor in different organs and tissues suggests that the DP receptor may be an attractive target for different therapeutic areas. It is particularly interesting that the DP receptor has been implicated in various inflammatory disorders including, but not limited to, asthma, allergic rhinitis, airway hyperactivity, allergic dermatitis, allergic conjunctivitis, and chronic obstructive pulmonary disease. This is supported by the observation that PGD2 is the major prostanoid released by immunologically challenged mast cells (Roberts, et al., 1980). In asthma, respiratory epithelium has long been recognized as a key source of inflammatory cytokines and chemokines that stimulate the progression of the disease (Holgate et al., 2000). In a murine model of experimental asthma, the DP receptor is dramatically regulated in an increasing sense in the epithelium of the airways during the confrontation with an antigen (Matsuoka et al., 2000). Conversely, in mice with a knockout gene lacking the DP receptor, there is a marked reduction in airway hyperreactivity and chronic inflammation (Matsuoka et al., 2000); two of the cardinal characteristics of human asthma. Similarly, it has been shown that DP receptor antagonists reduce airway inflammation in an experimental asthma model in the guinea pig (Arimura et al., 2001). It is also believed that the DP receptor is involved in human allergic rhinitis, a common allergic disease characterized by symptoms of sneezing, itching, runny nose and nasal congestion. Local administration of PGD to the nose causes a dose-dependent increase in nasal congestion (Doyle et al., 1990). DP antagonists have been shown to be effective in relieving the symptoms of allergic rhinitis in multiple species, and, more specifically, they have been shown to inhibit antigen-induced nasal congestion, the most overt symptom of allergic rhinitis. . DP antagonists are also effective in experimental models of allergic conjunctivitis and allergic dermatitis (Arimura et al., 2001). Thus, DP antagonists could therefore be useful in the treatment of a variety of disorders mediated by PGD2 including, but not limited to, bronchial asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis, allergic dermatitis, allergic conjunctivitis. , systemic mastocytosis and ischemic reperfusion injury. Until now, the DP receptor has been cloned from humans (Boie et al., 1995), rats (Wright et al., 1999) and mice (Hirata et al., 1994). These DP receptors share 73-90% homology at the amino acid level between humans, mice and rats and, in all cases, the activation of the recombinant receptors leads to the accumulation of intracellular cAMP. It has been generally observed among the G protein-coupled receptors that the compounds often exhibit variable potencies from one orthologous receptor to another. In this specification a guinea pig DP receiver is described for the first time. The present invention provides several advantages over what is currently known in the art. Differences in species between mouse, rat, human and guinea pig can now be determined and characterized more fully. The low levels of DP receptor expression in natural tissues make it difficult to assess the activity of a compound as a modulator, effector, agonist or receptor antagonist. The present invention now provides the opportunity to examine the receptor in an isolated and purified condition that provides the ability to assay compounds and then bridge the in vitro studies for the same species in vivo. Due to its larger size, the guinea pig is a preferred animal model for smaller rodents, providing for example a greater surface area in relation to dermatology and gastrointestinal studies. And, what is more important, the guinea pig is the most usable small animal model for some allergy models such as nasal congestion and is more sensitive to manipulations of airway hyperactivity. Although the guinea pig represents an ideal preclinical model for the evaluation of DP receptor modulators in multiple disease models, as discussed above, the cloning of the guinea pig DP receptor has not been reported so far and therefore it is difficult to predict affinity of a compound against this ortholog. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows a nucleic acid sequence of the receptor of the invention (SEQ ID NO: 1). Figure 2 shows an amino acid sequence of the receptor of the invention (SEQ ID NO: 2). Figure 3 shows an alignment of the DP receptor coding sequences among multiple species. The shaded residues exactly match the guinea pig residues. Hs = human; Rn = rat; Mm = mouse; and Cp = guinea pig. Figure 4 shows an alignment of the amino acid sequences of the DP receptor among multiple species. The shaded residues match the guinea pig residues exactly. Hs = human; Rn = rat; Mm = mouse; Cp = guinea pig. Figure 5 shows a Northern blot analysis of a genomic DNA fragment of the Ca-via porcellus DP receptor. Lane 1: RNA ladder of 0.24-9.5 Kb Invitrogen; lane 2: total lung RNA of Cavia porcellus not facing; lane 3: Total lung RNA of Cavia porcellus facing ovalbumin. Figure 6 shows an example of the PGD2-induced calcium mobilization of the guinea pig recombinant DP receptor expressed in stably transfected HEK-293-Gal6 cells compared to a line of equivalent cells generated with the mouse DP detector and the mouse line. parental cells. Figure 7 shows an example of the dose response curve of PGD2 of the guinea pig recombinant DP receptor expressed in HEK-293-Gal6 cells stably transfected using the cAMP SPA assay. The comparison is included with an equivalent cell line generated with the mouse DP receptor and the parental cell line. DETAILED DESCRIPTION OF THE INVENTION The present invention refers to isolated forms of nucleic acid and protein that represent, but are not necessarily limiting, the family of prostanoid receptors. In a preferred embodiment, the isolated nucleic acid and protein represent the DP receptor of the guinea pig. Various aspects of the invention are described in greater detail in the following subsections. Definitions As used herein, "nucleic acid molecule" refers to the polymer form of the ribosomal phosphate ester (adenosine, guanosine, uridine or cytidine, "RNA") or deoxyribonucleoside (deoxyadenosine, deoxyguanosine). , deoxythymidine, or deoxycytidine; "DNA") or any analogs of phosphoric esters thereof, such as phosphorothioates and thioesters, in single-chain form, or in the form of a double-stranded helix. The nucleic acid molecule can include a molecule of deoxyribonucleic acid (DNA), such as genomic DNA and complementary DNA (cDNA) which can be single-stranded or bicarbial-encoding or non-coding, synthetic DNA, ribonucleic acid (RNA) molecule it can be single-stranded or double-stranded and DNA and RNA analogs generated using nucleotide analogues. Bi-catenary helices are possible DNA: DNA, DNA: RNA and RNA: RNA. As used herein, an "isolated" or "purified" nucleic acid molecule is one that is separated from other nucleic acid molecules that are present in the natural source of the nucleic acid. Preferably, the "isolated" nucleic acid is free of sequences (preferably protein coding sequences) that naturally flank the nucleic acid (i.e., sequences located at the 5 'and 31 ends of the nucleic acid) in the genomic DNA of the organism from which the nucleic acid is derived. In various embodiments, the isolated nucleic acid molecule can contain less than about 5 kb, 4 kb, 3 kb, 2 kb, 1 kb, 0.5 kb or 0.1 kb of the nucleotide sequences flanking the nucleotide molecule of the present invention. For example, these flanking nucleotide sequences may be sequences that naturally flank the nucleotide molecule in the genomic DNA of the cell from which the nucleic acid was isolated. A nucleic acid can be considered isolated when it has been substantially separated from its endogenous environment to allow manipulation by one skilled in the art, such as, but not limited to, nucleotide sequencing, restriction digestion, targeted mutagenesis, and subcloning in expression vectors. The nucleic acid may be present in whole cells or cell lysates or in partially purified or substantially purified form. A nucleic acid purified from cells is substantially free of other cellular material or culture medium. A chemically synthesized nucleic acid is purified when it is substantially free of chemical precursors or other chemicals. The term "recombinant", when used in connection with a polypeptide, refers to a polypeptide derived by the translation of a recombinant polynucleotide., ie, a polynucleotide that is isolated or purified (as defined above), or that for any other reason is not in its natural state. The term includes, for example, those polypeptides that are expressed by or contained in cells that contain a cyanogenesis vector or expression vector, as well as synthetic polypeptides. As used herein, the term "modulator" refers to a moiety (e.g., but without limitation, a ligand and a candidate compound) that modulates the activity of the receptor protein of the present invention. A modulator of the present invention can be an agonist, a partial agonist, an antagonist, or an inverse agonist. As used herein, the term "agonist" refers to residues (eg, but not limited to ligands and candidate compounds), which activate the intracellular response when they bind to the receptor, or improve the binding of GTP to the membranes. . As used herein, the term "partial agonist" refers to residues (eg, but not limited to, ligands and candidate compounds) that activate the intracellular response when they bind to the recipient to a lesser extent / extent than they do. the agonists, or improve the GTP fixation to the membranes to a lesser degree / extension than the agonists do. As used herein, the term "antagonist" refers to residues (e.g., but without limitation, ligands and candidate compounds) that competitively bind to the receptor at the same site as an agonist does. However, an antagonist does not activate the intracellular response initiated by the active form of the receptor and can therefore inhibit intracellular responses by agonists or partial agonists. In a related aspect, the antagonists do not decrease the intracellular response of the baseline in the absence of an agonist or partial agonist.

As used herein, the term "inverse agonist" refers to residues (e.g., but without limitation, ligands and candidate compounds), which bind to a constitutively active receptor and inhibit the intracellular response of the baseline. The baseline response is initiated by the active form of the receptor below the normal base level of activity that is observed in the absence of agonists or partial agonists, or decreased GTP binding to the membranes. As used herein, the term "candidate compound" refers to a moiety (e.g., but without limitation, a chemical compound) that is suitable for a classification method. In one embodiment, the term does not include compounds that were publicly known as compounds selected from the group consisting of agonists, partial agonists, inverse agonists or antagonists. Said compounds have been identified by traditional drug discovery processes involving the identification of a specific endogenous ligand for a receptor, and / or the screening of candidate compounds against a receptor, wherein said screening requires a competitive assay to evaluate the effectiveness. As used herein, the terms "constitutively activated receptor" or "autonomously active receptor" are used interchangeably herein, and refer to a receptor subject to activation in the absence of a ligand. Such constitutively active receptors can be endogenous or non-endogenous (i.e., GPCRs can be modified by recombinant means to produce constitutive mutant forms of wild-type GPCRs, eg, see EP 1071701, WO 00/22129, WO 00/22131 and US Patents Núms. 6,150,393 and 6,140,509 which are hereby incorporated by reference in their totals). As used herein, the term "constitutive activation of a receptor" refers to the stabilization of a receptor in the active state by means other than receptor binding to the endogenous ligand or chemical equivalent thereof. As used herein, the term "ligand" refers to a moiety that is attached to another molecule, wherein the moiety includes, but is certainly not limited to, a hormone or neurotransmitter, and additionally, wherein the rest is fixed stereoselectively to a receiver. As used herein, the term "family", when referring to a protein or a nucleic acid molecule of the invention, is intended to mean two or more proteins or nucleic acid molecules having a structural domain apparently common and having sufficient identity in the amino acid or nucleotide sequence as defined herein. Members of such families may be naturally existing and may be of the same or different species. For example, a family may contain a first protein of human origin and a homologue of said protein of murine origin, as well as a second protein of different human origin and a murine homologue of said second protein. The members of a family may also have common functional characteristics. As used interchangeably herein, the terms "activity", "biological activity" and "functional activity" refer to an activity exerted by a protein, a polypeptide or a nucleic acid molecule of the present invention on a sensitive cell as determined in vivo or in vitro, according to standard methods. An activity may be a direct activity, such as an association with or an enzymatic activity on a second protein or an indirect activity, such as a cell signaling activity mediated by interaction of the protein of the present invention with a second protein. In a particular embodiment, an activity includes, but is not limited to, at least one or more of the following activities: (i) the ability to interact with proteins in the signaling path; (ii) the ability to interact with a ligand; and (iii) the ability to interact with an intracellular target protein. Additionally, in accordance with the present invention, conventional molecular biology, microbiology, and recombinant DNA methods can be employed within the skill of the art. These methods are explained in detail in the bibliography. See, e.g. , Sambrook, Fritsch & Maniatis, Molecular Cloning: A Laboratory Manual, Second Edition (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York (hereinafter referred to as "Sambrook et al., 1989"), - DNA Cloning: A Practical Approach, Volumes I and II (DN Glover, compiler, 1985); Oligonucleotide Synthesis (M.J. Gait, compiler, 1984); Nucleic Acid Hybridization [B.D. Hames & S.J. Higgins, compilers (1985)]; Transcription and Translation [B.D. Hames & S.J. Higgins, compilers (1984)]; Animal Cell Culture [R.I. Freshney, compiler (1986)]; Immobilized Cells And Enzymes [IRL Press, (1986)]; B. Perbal, A Practical Guide to Molecular Cloning (1984); F.M. Ausubel et al. (compilers), Current Protocols in Molecular Biology, John Wiley & Sons, Inc., (1994)).

A "vector" is a replicon, such as a plasmid, phage or cosmid, to name only a few, to which another DNA segment may be attached in order to perform the replication of the attached segment. A "replicon" is any genetic element (e.g., plasmid, chromosome, virus) that functions as an autonomous unit of DNA replication in vivo, that is, capable of replication under its own control. Particular examples of vectors are described infra. A "cassette" refers to a segment of DNA that can be inserted into a vector at specific restriction sites. The DNA segment encodes a polypeptide of interest, and the cassette and restriction sites are designed to ensure the insertion of the cassette into the appropriate reading frame for transcription and translation. A cell has been "transfected" by exogenous or heterologous DNA when said DNA has been introduced into the interior of the cell. A cell has been "transformed" by exogenous or heterologous DNA when the transfected DNA makes a phenotypic change. Preferably, the transforming DNA should be integrated (covalently linked) into the chromosomal DNA that constitutes the genome of the cell. "Heterologous" DNA refers to DNA not naturally located in the cell, or at a chromosomal site in the cell. Preferably, the heterologous DNA includes a gene foreign to the cell. "Homologous recombination" refers to the insertion of a foreign DNA sequence from a vector into a chromosome. In particular, the vector is directed to a specific chromosomal site for homologous recombination. For specific homologous recombination, the vector will contain sufficiently long homology regions to chromosome sequences to allow complementary binding and incorporation of the vector into the chromosome. Longer regions of homology, and greater degrees of sequence similarity, may increase the efficiency of homologous recombination. Isolated Nucleic Acid Molecules One aspect of the invention refers to isolated or purified nucleic acid molecules that encode the receptor proteins of the invention or portions thereof. The nucleic acid molecule of the present invention or a complement of the nucleic acid sequence can be isolated using standard methods of molecular biology and the sequence information provided in the present invention. Using all or a portion of the nucleic acid sequence of SEQ ID NO: 1 as a hybridization probe, the nucleic acid molecules of the invention can be isolated using standard methods of hybridization and cloning (Sambrook et al., 1989) . Oligonucleotides corresponding to SEQ ID NO: 1, or a portion thereof, can be prepared by standard synthetic methods, e.g., using an automatic DNA synthesizer. The nucleic acid molecule of the invention, or part thereof, can be amplified using cDNA, mRNA or genomic DNA as template and appropriate oligonucleotide primers according to standard methods of PCR amplification. The nucleic acid molecule of the invention may comprise a portion of SEQ ID NO: 1. The nucleic acid fragment can be used as a probe or primer or the fragment can encode a protein fragment that may or may not be a biologically active portion of the receptor such as the ligand binding domain. For example, it was proposed that arginine in the seventh transmembrane domain was the binding site for the carboxyl group of the prostanoid molecule (Narumiya et al., 1993) and Lys-75 and Leu-83 of the second transmembrane domain in the mouse confer ligand binding specificity (Kobayashi et al., 2000). It has been previously reported that these two sequence stretches are characteristically conserved among the GPCRs of the prostanoid family (Hirata et al., 1994) and are also present in the guinea pig DP protein: QYCPTGWCR in the second extracellular loop and RFLSVISIVDPWIFI in the seventh transmembrane domain were identical among all DP orthologs. The nucleotide sequence of SEQ ID N0: 1 allows the generation of probes and primers for the use of identification and / or cloning of the receptor of the invention or homologs thereof in cells, tissues and organs. The oligonucleotide typically comprises a nucleotide sequence region that hybridizes under severe conditions to at least 10, preferably approximately 12, more preferably 25, 50, 75, 100, 125, 150, 175, 200, 250, 300 , 350 or 400 consecutive nucleotides of the sense or antisense sequence of SEQ ID NO: 1, or of a naturally occurring or artificial mutation of SEQ ID NO: 1. The probe may comprise a label group attached thereto, e.g., a radioisotope, a fluorescent compound, an enzyme or an enzymatic co-factor. The probe can be part of a kit for identification of cells or tissues encoding the nucleic acid, detection of mRNA levels or determination of whether a genomic gene has undergone mutation or deletion. The present invention extends further to an isolated nucleic acid molecule having 90% homology to SEQ ID NO: 1. Sequences that are substantially homologous can be identified by comparison of the sequences using standard software available in sequence data banks using default parameters, or in a Southern hybridization experiment, for example, under severe conditions as defined for that particular system. The definition of the appropriate hybridization conditions is within the skill in the art. See, e.g., Maniatis et al., Supra; DNA Cloning, Vols. I & II, supra; Nucleid Acid Hybridization, supra. DNA sequence polymorphisms may exist within a population due to natural allelic variation. An allele is a group of genes that occur alternately at a given genetic locus. As used herein, the terms "gene" and "recombinant gene" refer to nucleic acid molecules comprising an open reading frame encoding the receptor protein of the invention, preferably a guinea pig receptor protein. As used herein, the phrase "allelic variant" refers to a nucleotide sequence that is located at the locus of the gene or to a polypeptide encoded by the nucleotide sequence. Alternative alleles can be identified by sequencing the gene of interest in a number of different individuals. Any and all such nucleotide variations and polymorphisms resulting from amino acids or variations that are the result of natural allelic variation and which do not alter the functional activity of the receptor of the invention should be considered included within the scope of the invention. A nucleic acid fragment encoding a "biologically active" or "biologically relevant" portion can be prepared by isolation of a portion of SEQ ID NO: 1 encoding a polypeptide having the biological activity of the receptor of the invention. For example, the expression of the encoded portion of the receptor protein (e.g., by in vitro recombinant expression) of the ligand binding domain or the signal transduction domain and subsequent evaluation of the activity of said encoded portion of the receptor. The invention further encompasses nucleic acid molecules that differ from the nucleotide sequence of SEQ ID NO: 1 due to the degeneracy of the genetic code and thus encode the same protein as that encoded by the nucleotide sequence of SEQ ID N0.-1. . For example, the inventors have identified two potential N glycosylation sites, Asn-7 at the amino terminus and Asn-86 at the first extracellular loop. Additionally, there are also two potential phosphorylation sites of protein kinase C, Ser-46 and Thr-140 located in the first and third cytoplasmic loops, respectively. In addition to naturally occurring allelic variants, it is known to those skilled in the art that there is a substantial amount of redundancy in the various codons that encode specific amino acids. Thus, the invention is directed to those RNA coding DNA sequences comprising alternative codons or RNA sequences coding for alternative codons encoding the eventual translation of the identical amino acid sequence of SEQ ID NO: 2 or portions thereof. It is well known in the art that the following codons can be used interchangeably to code for each specific amino acid: Phenylalanine (Phe or F) UUU or UUC Leucine (Leu or L) UUA or UUG or CUU or CUC or CUA or CUG Isoleucine (He or I) AUU or AUC or AUA Methionine (Met or M) AUG Valine (Val or V) GUU or GUC or GUA or GUG Serine (Ser or S) UCU or UCC or UCA or UCG or AGU or AGC Proline (Pro or P) CCU or CCC or CCA or CCG Threonine (Thr or T) ACU or ACC or ACÁ or ACG Alanine (Wing or A) GCU or GCG or GCA or GCG Thyrosine (Tyr or Y) UAU or UAC Histidine ( His or H) CAU or CAC Glutamine (Gln or Q) CAA or CAG Asparagine (Asn or N) AAU or AAC Lysine (Lys or K) AAA or AAG Aspartic acid (Asp or D) GAU or GAC Glutamic acid (Glu or E) ) GAA or GAG Cysteine (Cys or C) UGU or UGC Arginine (Arg or R) CGU or CGC or CGA or CGG or AGA or AGG Glycine (Gly or G) GGU or GGC or GGA or GGG Tryptophan (Trp or W) UGG Coating termination UAA or UAG or UGA It should be understood that the above-specified codons are for RNA sequences. The corresponding codons for DNA have a T in place of U. A person skilled in the art can further appreciate that changes in SEQ ID NO: 1 can be introduced by mutation without altering the biological activity of the encoded protein. A "non-essential" amino acid residue is a residue that can be altered from the wild-type sequence, eg, the sequence of SEQ ID NO: 2 without altering the biological activity, while the "essential" amino acid residues are necessary for the biological activity. Thus, amino acid residues that are not conserved or are only semi-preserved between different species may be non-essential and likely targets for alteration. Another aspect of the invention relates to nucleic acid molecules that encode proteins of the invention that contain changes in amino acid residues that are not essential for activity. Such proteins differ in the amino acid sequence of SEQ ID NO: 1, but retain the biological activity. An isolated nucleic acid molecule encoding a protein having a sequence that differs from that of SEQ ID NO: 2 can be created by introducing one or more substitutions, additions or deletions of nucleotides in the nucleotide sequence of SEQ ID NO: 1. Mutations can be introduced by standard techniques such as site-directed mutagenesis and PCR-mediated mutagenesis. Preferably, conservative amino acid substitutions are made in one or more predicted nonessential amino acid residues. A "conservative amino acid substitution" is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues that have similar side chains have been defined in the art. For example, the families include amino acids with basic side chains (eg, lysine, arginine, histidine), acid side chains (eg, aspartic acid, glutamic acid), uncharged polar side chains (eg, glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), non-polar side chains (eg, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), side chains with branched-beta clones (eg, threonine, valine, isoleucine) and side chains aromatics (eg tyrosine, phenylalanine, tryptophan, histidine). The analysis of the guinea-pig receptor sequence provided later in "Example 3" comparing the sequence of the guinea pig with the human, rat and mouse sequences provides guidance in the selection of non-essential amino acids. Thus, a predicted non-essential amino acid residue would preferably be replaced with another amino acid residue of the same side chain family. Alternatively, mutations can be introduced randomly along the coding region or portions thereof, for example by saturation mutagenesis, and the resulting mutants can be screened for biological activity in order to identify mutants that retain the activity. After mutagenesis, the encoded protein can be expressed recombinantly and the activity of the protein can be determined. In a preferred embodiment, the mutant protein can be tested for the ability to cause protein: protein interactions for example with proteins in the signaling path of prostanoids; the ability to bind ligands such as ligands that bind to the prostanoid receptor; or, the ability to bind to intracellular proteins. The present invention also relates to native or mutant protein or protein fragments for diagnostic, therapeutic or prophylactic use and could be useful for the screening of agonists, antagonists or modulators of receptor function. Nucleotide sequences encoding a peptide can be altered in order to encode a protein having properties that are different from those of the naturally occurring peptide, for example changing affinity of the ligand binding domain or modulation of the signal transduction pathway. The present invention also relates to alterations of the nucleic acid sequence of SEQ ID NO: 1 or portions thereof that modify the biological activity of the protein. Hybridization of Isolated Nucleic Acid Molecules A nucleic acid molecule is "hybridizable" to another nucleic acid molecule, such as a cDNA, genomic DNA, or RNA, when a single-stranded form of the nucleic acid molecule can be reassociated with another molecule of nucleic acid. nucleic acid under the appropriate conditions of temperature and ionic concentration of the solution (see Sambrook et al., supra). The conditions of temperature and ionic concentration determine the "severity of the hybridization". The low stringency hybridization conditions correspond to a Tm value of 55 ° C. { v. g. , 5x sodium chloride / sodium citrate (SSC), 0.1% SDS, 0.25% milk, and absence of formamide; or 30% formamide, 5x SSC, 0.5% SDS). Hybridization conditions of moderate severity correspond to a higher Tm value (e.g., 40% formamide, with 5x or 6x SSC). The high severity hybridization conditions correspond to the maximum Tm value,. { e.g. , 50% formamide, 5x or 6x SSC). Hybridization requires that the two nucleic acids contain complementary sequences, although depending on the severity of the hybridization, mismatches between bases are possible. The appropriate severity for the hybridization of nucleic acids depends on the length of the nucleic acids and the degree of complementation, variables well known in the art. The greater the degree of similarity or homology between two nucleotide sequences, the greater the value of Tm for nucleic acid hybrids having such sequences. The relative stability (corresponding to a higher Tm value) of the nucleic acid hybridizations decreases in the following order: RNA: RNA, DNA: RNA, DNA: DNA. In the case of hybrids that are more than 100 nucleotides in length, equations have been derived for the calculation of Tm (see Sambrook et al., Supra 9.50-9.51). For hybridization with shorter nucleic acids, ie, oligonucleotides, the position of the mismatches becomes more important, and the length of the oligonucleotide determines its specificity (see Sambrook et al., Supra, 11.7-11.8). A minimum length for a hybridizable nucleic acid molecule is at least about 20 nucleotides; in particular at least about 30 nucleotides, more particularly at least about 40 nucleotides, still more particularly about 50 nucleotides, and more particularly still, at least about 60 nucleotides.

In a specific embodiment, the term "standard hybridization conditions" refers to a Tm value of 55 ° C, and uses conditions such as those set forth above. In a preferred embodiment, the value Tm is 60 ° C; in a more preferred embodiment, the value Tm is 65 ° C. In a particular embodiment of the present invention, a hybridizable nucleic acid molecule of the invention has a length of at least 300, 325, 350, 375, 400, 425, 450, 500, 550, 600, 650, 70, 800, 900 or 1000 nucleotides and hybridizes under severe conditions to the nucleic acid molecule comprising the nucleotide sequence, preferably the coding sequence, of SEQ ID NO: 1, a complement thereof, or a fragment thereof. The term "hybridizes under severe conditions" is intended to describe conditions for hybridization and washing in which nucleotide sequences having at least 55%, 60%, 65%, 70% and preferably 75% or more of complementarity a with respect to another, they are typically hybridized. Such severe conditions are known to those skilled in the art and can be found in "Current Protocols in Molecular Biology ", John Wiley &Sons, NY (1989), 6.3.1-6.3.6 A preferred and non-limiting example of severe hybridization conditions is hybridization in 6X SSC at approximately 45 ° C, followed by one or more washes in 0.2X SSC, 0.1% SDS at 50-65 ° C. Preferably, an isolated nucleic acid molecule of the invention that hybridizes under severe conditions to the sequence of SEQ ID NO: 1 to the complement it corresponds to a naturally occurring nucleic acid molecule, as used herein, a nucleic acid molecule "naturally occurring" refers to an RNA or DNA molecule having a nucleotide sequence that exists in nature (e.g., encodes a natural protein). One skilled in the art will appreciate that the conditions can be modified by taking into account specific sequence variables (e.g., length, richness in G-C, etc.). In another embodiment, an isolated nucleic acid molecule of the invention that hybridizes under severe conditions to a portion of the sequence of SEQ ID NO: 1 can be used as a probe or as an initiator. The probe or primer generally comprises a substantially purified oligonucleotide. The oligonucleotide typically comprises a region of the nucleotide sequence that hybridizes under severe conditions to at least about 12, preferably about 25, more preferably about 50, 75, 100, 125, 150, 175, 200, 250, 300, 350 or 400 consecutive nucleotides of the sense or antisense sequence of SEQ ID NO: 1 or of a naturally occurring mutant of SEQ ID NO: 1. Anti-Sense Nucleic Acid Molecules The present invention encompasses antisense nucleic acid molecules, ie, molecules that are complementary to a sense nucleic acid encoding a protein (v. g., complementary to the coding strand of a double-stranded cDNA molecule or complementary to a mRNA sequence). An antisense nucleic acid can be linked by hydrogen bonds to a sense nucleic acid. The antisense nucleic acid can be complementary to an entire nucleic acid sequence of SEQ ID NO: 1 or a portion thereof. Given the sequences of the coding strand described herein (e.g., SEQ ID N0: 1), the antisense nucleic acids of the invention may be de-signed according to the Watson & Crick. An antisense oligonucleotide can have, for example, a length of about 5, 10, 15, 20, 25, 30, 35, 40, 45 or 50 nucleotides. A nucleic acid antisense of the invention can be constructed using chemical synthesis and enzymatic ligation reactions using procedures known in the art. For example, an antisense nucleic acid (eg, an antisense oligonucleotide) can be chemically synthesized using naturally occurring oligonucleotides or various chemically modified nucleotides, designed to increase the biological stability of the molecules, or to increase the physical stability of the duplex formed between the molecules. antisense and sense nucleic acids; e.g., phosphorothioate derivatives, phosphonate derivatives and acridine-substituted nucleotides can be used. Examples of modified nucleotides that can be used to generate the antisense nucleic acid include 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodo-uracil, hypoxanthine, xanthine, 4-acetylcytosine, 5- (carboxyhydroxymethyl) uracil, 5-carboxymethylaminomethyl -2-thiouridine, 5-carboxymethylaminomethyluracil, dihydrou-lo,? -D ~ galactosylqueosine, inosine, N6-isopentenyladenine, 1-methylguanine, 1-methylinosine, 2,2-dimethylguanine, 2-methyladenine, 2-methylguanine, 3-methylcytosine , 5-methyl-cytosine, Ne-adenine, 7-methylguanine, 5-methylamino-methyluracil, 5-methoxyaminomethyl-2-thiouracil, / 3-D-mannosyl-keosine, 5-methoxycarboxymethyluracil, 5-methoxyuracil, 2-methylthio- Ns-isopentenyladenine, uracil-5-oxyacetic acid, wibutoxosine, pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil, 2-thiouracil, 4-thiouracil, 5-methyl-uracil, methyl ester of uracil-5 -oxyacetic acid, uracil-5-oxyacetic acid, 5-methyl-2-thiouracil, 3- (3-amino-3-N-2-carboxypropyl) uracil and 2,6-diaminopurine. Alternatively, the antisense nucleic acid can be produced biologically using an expression vector in which the nucleic acid has been subcloned in an antisense orientation (eg, RNA transcribed from the inserted nucleic acid will be of an antisense orientation to an acid target nucleic of interest). The antisense nucleic acid molecules of the invention are typically administered to an individual or generated in situ such that they hybridize with or bind to cellular mRNA and / or genomic DNA encoding the protein of the invention, inhibiting This is the expression of the protein by inhibition of transcription and / or translation. Hybridization can be done by conventional nucleotide complementarity to form a stable duplex, or, for example, in the case of an antisense nucleic acid, molecules that are fixed to DNA duplexes, by specific interactions in the larger groove of the double helix, or to a regulatory region. An example of a route of administration of antisense nucleic acid molecules of the invention includes direct injection into a tissue site. Alternatively, the antisense nucleic acid molecules can be modified for selected target cells and then administered systemically. For example, for systemic administration, the antisense molecules can be modified such that the molecules are specifically bound to reces or antigens expressed on a selected cell surface, e.g. by binding the antisense nucleic acid molecules to peptides or antibodies that bind to reces or cell surface antigens. Antisense nucleic acid molecules can also be delivered to cells using the vectors described herein. To achieve sufficient intracellular concentrations of the antisense molecules, constructs of vectors in which the antisense nucleic acid molecule is under the control of a strong poly II or pol III promoter are preferred. An antisense nucleic acid molecule of the invention can be an alpha-anomeric nucleic acid molecule. An alpha-anomeric nucleic acid molecule forms specific double-stranded hybrids with complementary RNA in the sense that the strands run parallel to each other (Gaul-tier et al., Nucleic Acids Res (1987) 15: 6625-6641). The antisense nucleic acid molecule can also comprise a methylribonucleotide (Inoue et al., Nucleic Acids Res (1987) 15: 6131-6148) or a chimeric RNA-DNA analog (Inoue et al., FEBS Lett (1987) 215: 327 -330). Ribozymes The invention also encompasses ribozymes. Ribozymes are catalytic RNA molecules with ribonuclease activity that are capable of cleaving a mono-catenary nucleic acid, such as an mRNA, that hybridizes to the ribozyme. Thus, ribozymes (e.g., hammerhead ribozymes (described in Haselhoff et al., Nature (1988) 334: 585-591)) can be used to catalytically cleave nucleic acid transcripts and thus inhibit mRNA translation corresponding to SEQ ID NO: 1. A ribozyme having specificity for the nucleic acid of SEQ ID NO: l can be designed on the basis of the nucleotide sequence of SEQ ID NO: 1. For example, a derivative of an IVS L-19 RNA of Tetrahymena can be constructed in such a way that the nucleotide sequence of the active site is complementary to the nucleotide sequence to be excised on the basis of the reported nucleic acid sequence of SEQ ID NO. : l (US Pat. Nos. 4,987,071 and 5,116,742, the descriptions of which are incorporated by reference). Alternatively, the nucleic acid sequence of SEQ ID NO: 1 can be used to select a catalytic RNA having a specific ribonuclease activity "from a pool of RNA molecules (Bartel et al., Science (1993) 261). : 1411-1418). Triple Helical Nucleic Acid and Peptide Nucleic Acid Molecules The invention also encompasses nucleic acid molecules that form triple helical structures, eg, gene expression can be inhibited by targeting nucleotide sequences complementary to the region. regulator of SEQ ID N0: 1 (eg, the promoter and / or enhancer region) to form triple helical structures that prevent gene transcription in target cells, see generally, Helene, Anticancer Drug Des (1991) 6 (6): 569; Helene Ann NY Acad Sci (1992) 660: 27; and Maher, Bioas-says (1992) 14 (12): 807. In particular embodiments, the nucleic acid molecules of the invention can be modified in the base moiety, the sugar moiety or the phosphate backbone to improve, eg, the stability, hybridization or solubility of the molecule. For example, the deoxyribose-phosphate backbone of the nucleic acids can be modified to generate peptide nucleic acids (see Hyrup et al., Bioorganic &Medicinal Chemistry (1996) 4: 5). As used herein, the terms "peptide nucleic acids" or "PNAs" refer to nucleic acid mimetics, eg, DNA mimics, in the sense that the deoxyribose phosphate backbone is replaced by a pseudopeptide backbone and only the four natural nucleobases are retained. It has been demonstrated that the neutral main chain of the PNAs allows the specific hybridization to DNA and RNA in conditions of low ionic concentration. Synthesis of PNA oligomers can be performed using standard protocols of solid-phase peptide syn thesis as described in Hyrup et al. (1996) supra; Perry-0 'Keefe et al., Proc Nati Acad Sci USA (1996) 93: 14670. PNAs can be used in therapeutic and diagnostic applications. For example, PNAs can be used as antisense or antigenic agents for specific modulation of the gene expression sequence by, e.g., induction of transcription or translation stoppage or replication inhibition. PNAs of the present invention can also be used. For example, a PNA can be used in the analysis of single-base pair mutations in a gene by, e.g., PCR clamping by PNA; as artificial restriction enzymes when used in combination with other enzymes, eg, nucleases SI (Hyrup et al (1996) supra) or as probes or primers for DNA hybridization and sequence (Hyrup et al. (1996) supra); Perry-0 'Keefe et al. (1996) supra). In another embodiment, the PNAs of the present invention can be modified, eg, to increase the stability, specificity or cellular uptake, by binding of lipophilic groups or other adjuvant groups to the PNA, by the formation of PNA-DNA chimeras or by the use of liposomes or other methods of drug delivery known in the art. The synthesis of PNA-DNA chimeras can be performed as described in Hyrup et al. (1996) supra, Finn et al., Nucleic Acids Res (1996) 24 (17): 3357-63, Mag et al., Nucleic Acids Res (1989) 17: 5973; and Peterser et al., Bioorganic Med Chem Lett (1975) 5: 1119. RNA / Nucleic Acid Interference RNA interference (RNAi) or nucleic acid interference (NAi) is a process of silencing genes specific to the sequence subsequent to transcription mediated by short interfering RNAs (siRNAs) or short interfering nucleic acids (siNA). It is believed that this process is an evolutionarily conserved defense mechanism by which the production of double-stranded RNAs (dsRNAs) or double-stranded nucleic acids (dsNA), for example as a result of viral infection, stimulates the activity of a ribonuclease III enzyme to which it is referred to as dicer (Berstein et al., 2001, Nature 409: 363). For example, Dicer processes the dsRNA in siRNA. Dicer may be involved in the cleavage of small temporal RNAs of 21 and 22 nucleotides (stRNAs) involved in the control of translation. The RNAi response also involves an endonuclease complex, an RNA-induced silencing complex (RISC), which cleaves the single-stranded target RNA having a sequence complementary to the antisense strand of siRNA (Elbashir et al., 2001, Genes Dev. , 15: 188). The optimal design of siRNAs, dsRNAs, siNAs or dsNAs based on length, structure, chemical composition and sequence for efficient RNAi or NAi known to those skilled in the art (for examples, see Chiu and Rana et al., 2003, RNA 9: 1034-48; Elbashir et al., 2001, Parish et al., 2000; PCT Publications Nos. WO 03/070744, WO 01/75164, WO 01/68836, WO 01/49844, WO 01/36646, WO 01/29058, WO 00/44914, WO 00/01846, WO 99/32619, WO 99/07409, WO 99/53050; and Canadian Patent Application No. 2,359,180, the descriptions of which are incorporated by reference). Some possible modifications of siNA or dsNA to improve activity include, but are not limited to: 3 'terminal dinucleotide pendants, replacement of one or both siNA chains with 2'-deoxy-nucleotides (2'-H), replacement of the pendant nucleotide segments of terminal 31 of the siNA duplex with deoxyribonucleotides, modifications of the phosphate-sugar or nucleoside backbone to include at least one of a nitrogen or sulfur heteroatom, 2'-amino or 2'-O -methyl-nucleotides and nucleotides containing a 2'-O or 4'C-methylene bridge in dsRNA constructs, substitution of 4-thiouracil, 5-bromouracil, 5-iodouracil and 3- (aminoalyl) uracil in sense and antisense PCT Publication No. WO 01/68836 discloses methods for using endogenously derived dsRNA in order to attenuate gene expression. Additionally, it has been suggested that the mRNA targeted for RNAi acts as a template for the synthesis of 5 'to 3' of new dsRNA directed to a gene in a single cell type and can lead to RNAi-mediated silencing of a second gene expressed in a different type of cell, a phenomenon called transitive RNAi (Alder et al., 2003, rna 9: 25). Protein The present invention extends to an isolated polypeptide comprising the amino acid sequence of SEQ ID NO: 2, a variant thereof, a fragment thereof or an analog or derivative thereof. An isolated nucleic acid molecule encoding a protein of the present invention having a sequence that differs from that of SEQ ID NO: 2, e.g. a variant may be created by introducing one or more substitutions, additions or deletions of nucleotides in the nucleotide sequence of SEQ ID NO: 1 such that one or more substitutions, additions or deletions of amino acids are introduced into the encoded protein. For example, the first and third intracellular loops are three and five short amino acids in guinea pig DP protein, respectively, whereas in mouse, human and rat DP proteins these intracellular loops are all of identical size. A variant of SEQ ID NO: 2 could be created by inserting one or more nucleotides found in any of the other orthologs.

In a particular embodiment, a mutant protein of the present invention can be tested for: (1) the ability to cause protein: protein interactions with proteins comprised in the signaling path; (2) the ability to bind to a ligand; (3) the ability to bind to an intracellular target protein, or (4) the ability to modulate cell proliferation, cell differentiation or cellular response. The native proteins of the invention can be isolated from cells or tissue sources by an appropriate purification template using standard protein purification techniques. Alternatively, the proteins of the invention can be easily produced by recombinant DNA techniques. Another alternative embodiment is the chemical synthesis of the protein or polypeptide of the invention using standard techniques of peptide synthesis.

Biologically active portions or fragments of a protein of the invention include peptides comprising amino acid sequences sufficiently identical to or de-derived from the amino acid sequence of SEQ ID NO: 2, which include fewer amino acids than the full-length protein of the invention and they exhibit at least one activity of the protein of the invention. Typically, the biologically active portions comprise a domain or motif with at least one activity of the protein of the invention. For example, a biologically active fragment of the protein of the invention could contain two previously conserved sequence stretches that are characteristically conserved among the GPCRs of the prostanoid family (Hirata et al., 1994) and are also present in the guinea pig DP protein: QYCPGTWCR in the second extracellular loop and RFLSVISIVDPWIFI in the seventh transmembrane domain. A biologically active portion of the protein of the invention may be a polypeptide having a length of, for example, 10, 25, 50, 100 or more amino acids. Particular biologically active polypeptides include one or more structural domains identified from the protein of the present invention. In addition, other biologically active portions, in which other regions of the protein have been deleted, can be prepared by recombinant techniques and evaluated for one or more of the functional activities of the protein of the invention. Additional orientations directed to biologically relevant portions of the invention are provided later in "Example 3". Other useful proteins are substantially identical to SEQ ID No: 2 and retain a functional activity of the protein of SEQ ID No: 2 but differ in amino acid sequence due to natural allelic variation or mutagenesis. For example, such proteins and polypeptides possess at least one biological activity described herein. Accordingly, a useful protein of the invention is a protein that includes an amino acid sequence that is about 65%, 75%, 85%, 95%, 99% or 100% identical to the amino acid sequence of SEQ ID No : 2 and retains a functional activity of the SEQ ID No: 2 protein. To determine the percent identity of two amino acid or two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (eg, they can be introduced discontinuities in the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second amino acid or nucleic acid sequence). The amino acid or nucleotide residues are then compared at corresponding amino acid positions or nucleotide positions. When a position in the first sequence is occupied by the same amino acid or nucleotide residue as the corresponding position in the second sequence, then the molecules are considered identical in that position. The percentage of identity between the two sequences is a function of the number of identical positions shared by the sequences (ie, identity percentage = number of identical positions / total number of positions (e.g., overlapping positions) x 100). In one embodiment, the two sequences have the same length. The determination of the identity percentage of two sequences can be done using a mathematical algorithm. A particular, non-limiting example of a mathematical algorithm used for the comparison of two sequences is the algorithm of Karlin et al. , Proc Nati Acad Sci USA (1990) 87: 2264, modified as in Karlin et al., Proc Nati Acad Sci USA (1993) 90: 5873-5877. An algorithm of this type is incorporated in the NBLAST and XBLAST programs of Altschul et al. , J Mol Bio (1990) 215: 403. To obtain discontinuous alignments for comparison purposes, Gapped BLAST can be used as described in Altschul et al., Nucleic Acids Res (1997) 25: 3389. Alternatively, PSI-Blast can be used. to perform an iterated search that detects distant relationships between molecules. Altschul et al. (1997) supra. When the BLAST, Gapped BLAST and PSI-Blast programs are used, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used, see http://www.ncbi.nlm.nih.gov. Another particular, non-limiting example of a mathematical algorithm used for the comparison of sequences is the algorithm of Myers et al., CABIOS (1988) 4: 11-17. An algorithm of this type is incorporated into the ALIGN program (version 2.0) that is part of the GCG sequence alignment software package. When using the ALIGN program for comparison of amino acid sequences, a waste weight table PAM120, a discontinuity length penalty of 12 and a discontinuity penalty of 4 can be used. The percent identity between two sequences can be determined using techniques similar to those described above, with or without tolerance of discontinuities. In the calculation of the percentage of identity, only the exact matings are counted. The present invention extends further to chimeric or fusion proteins of the invention. As used herein, a "chimeric protein" or "fusion protein" of the invention comprises a polypeptide of SEQ ID No: 2 operably linked to a "polypeptide not belonging to the invention". A "polypeptide of the invention" refers to a polypeptide having an amino acid sequence corresponding to SEQ ID No: 2. A "polypeptide not belonging to the invention" refers to a polypeptide having an amino acid sequence corresponding to a protein which is not substantially identical to SEQ ID No. 2, eg, a protein that is different from the protein of the invention and that is derived from the same organism or a different organism. In a fusion protein of the invention, the polypeptide of the invention may correspond to all or a portion of a SEQ ID No: 2, preferably at least a biologically active portion of a SEQ ID No: 2. In the protein For the purpose of fusion, the term "operatively linked" is intended to indicate that the polypeptide of the invention and the polypeptide not detrimental to the invention are fused in frame with respect to one another. The polypeptide not belonging to the invention can be fused to the N-terminus or the C-terminus of the polypeptide of the invention. A useful fusion protein utilizes glutathione-S-transferase (GST) in which the polypeptide of the invention is fused to the C-terminus of GST. Such fusion proteins can facilitate the purification of the recombinant polypeptides of the invention. In another embodiment, a fusion protein of the present invention is extended to an immunoglobulin fusion protein in the sense that all or a portion of SEQ ID No: 2 is fused to sequences derived from a member of the family of the immunoglobulin proteins. The immunoglobulin fusion protein of the invention can be incorporated into pharmaceutical compositions and administered to an individual to inhibit an interaction between a ligand and the receptor protein of the invention on the surface of a cell, thereby suppressing signal transduction mediated by the receptor in vivo. The immunoglobulin fusion protein of the invention can be used to affect the bioavailability of an affinity ligand of the receptor of the present invention. The inhibition of the ligand-receptor interaction may be therapeutically useful, such as, but not limited to, the treatment or modulation of sleep, body temperature, olfactory function, hormone release, pain, disorders of the gastrointestinal tract, liver disease, ophthalmic diseases such as glaucoma, blood disorders such as thrombosis, inflammatory disorders including but not limited to asthma, allergic rhinitis, airway hyperactivity, allergic dermatitis, allergic conjunctivitis, and obstructive pulmonary disease chronicle. In addition, the immunoglobulin-polypeptide fusion proteins of the invention can be used as immunogens to produce antibodies in an individual, to purify ligands and in screening assays to identify molecules that inhibit the interaction of the receptor of the invention with a ligand. . In a particular embodiment, a chimeric or fusion protein of the present invention is produced by standard recombinant DNA techniques. For example, DNA fragments encoding the different polypeptide sequences are ligated together in frame according to conventional techniques, for example, by using terms with blunt ends or with cohesive ends for ligation, digestion with restriction enzymes in order to provide Appropriate terms, filling of cohesive ends where appropriate, treatment with alkaline phosphatase to avoid undesirable enzymatic binding and ligation. In another embodiment, the fusion gene can be synthesized by conventional techniques including automatic DNA synthesizers. Alternatively, PCR amplification of gene fragments can be carried out using anchoring primers that give rise to complementary pendants between two consecutive gene fragments that can subsequently be reassociated and reamplified to generate a chimeric gene sequence (see, eg, Ausubel). et al., supra). In addition, many expression vectors that already encode a fusion moiety (e.g., a GST polypeptide) are commercially available. A nucleic acid encoding the polypeptide of the invention or a portion thereof can be cloned into an expression vector of this type such that the fusion protein is bound in frame to the protein of the invention. Variants of Nucleic Acids and Proteins As explained above, the present invention extends further to variants of SEQ ID No: 1 and SEQ ID No: 2. For example, mutations can be introduced into the amino acid sequence of SEQ ID No: 1 using standard techniques, such as site-directed mutagenesis and PCR-mediated mutagenesis. In addition, conservative amino acid substitutions can be made in one or more predicted nonessential amino acid residues. A "conservative amino acid substitution" is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. For example, one or more amino acids can be substituted by another amino acid of a similar polarity, which acts as a functional equivalent, resulting in a silent alteration. Substitutes of an amino acid within the amino acid sequence of a polypeptide of the present invention can be selected from other members of the class to which the amino acid belongs. For example, non-polar (hydrophobic) amino acids include alanine, leucine, isoleu-ciña, valine, proline, phenylalanine, tryptophan, and methionine. Amino acids containing aromatic ring structures are phenylalanine, tryptophan and tyrosine. Neutral polar amino acids include glycine, serine, threonine, cysteine, tyrosine, asparagine and glutamine. The positively charged (basic) amino acids include arginine, lysine and histidine. The negatively charged amino acids (acids) include aspartic acid and glutamic acid. It is not expected that such alterations affect the apparent molecular weight as determined by electrophoresis in polyacrylamide gel, or by the isoelectric point. Particularly preferred substitutions are: - Lys instead of Arg and vice versa, whereby a positive charge can be maintained; - Glu instead of Asp and vice versa, with which a negative charge can be maintained; - Being instead of Thr, with which a free -OH can be maintained; - Gln instead of Asn, with which a free NH2 can be maintained. Additional substitutions can be made with synthetic amino acids (ie, not naturally occurring). Amino acid substitutions can also be introduced to substitute an amino acid with a particularly preferable property. For example, a Cys can be introduced in substitution of a potential site for disulfide bridges with another Cys. A His can be introduced as a particularly "catalytic" site (ie, His can act as an acid or base and is the most common amino acid in biochemical catalysis). Pro can be introduced due to its particularly planar structure, which induces ß-turns in the structure of the protein. Mutations can also be randomly introduced throughout all or part of a coding sequence of SEQ ID No-. 1, for example by saturation mutagenesis, and the resulting mutants can be screened for biological activity in order to identify mutants that retain activity. Following mutagenesis, the encoded protein can be expressed recombinantly and the activity of the protein can be determined. Variants of the present invention can function as an agonist (mimetic) or as an antagonist. Variants of the protein of the invention can be generated by mutagenesis, e.g. discrete point mutation or truncation of the protein of the invention. An agonist of the protein of the invention can retain substantially the same or a subset of the biological activities of the naturally occurring protein of the invention. An antagonist can be competitively bound to a member located downstream or upstream of a cellular signaling cascade including the protein of the invention, and thus inhibit one or more of the activities of the naturally occurring form in the protein of the invention. Thus, specific biological effects can be provoked by treatment with a variable of limited function. Treatment of an individual with a variant having a subset of the biological activities of the naturally occurring form of the protein of the invention may have fewer side effects in an individual as compared to treatment with the naturally occurring form of the protein. Variants of the protein of the invention that function as agonists (mimetics) or as antagonists can be identified by screening combinatorial libraries of mutants, e.g., truncation mutants, of the protein of the invention for agonist or antagonist activity. In one embodiment, a diversified library of variants of the protein of the invention is generated by combinatorial mutagenesis at the nucleic acid level, and is encoded by a diversified gene library. A variegated library of variants can be produced, for example, by enzymatic ligation of a mixture of synthetic oligonucleotides in gene sequences such that a degenerate set of potential nucleic acid sequences of the invention are expressed as individual polypeptides or alternatively, as a series of proteins. of larger fusion (eg, for phage display) containing in them the set of sequences of the invention. There are a variety of methods that can be used to produce libraries of potential variants of the invention from a degenerate oligonucleotide sequence. The chemical synthesis of a degenerate gene sequence can be performed in an automatic DNA synthesizer and the synthetic gene can then be ligated to an appropriate expression vector. The use of a degenerate set of genes allows the provision, in a single mixture, of all the coding sequences of the desired set of potential nucleic acid sequences of the invention. Methods for synthesizing degenerate oligonucleotides are known in the art (see, e.g., Narang, Tetrahedron (1983) 39: 3; Itakura et al., Ann Rev Biochem (1984) 53: 323.; Itakura et al., Science (1984) 198: 1056; Ike et al., Nucleic Acid Res (1983) 11: 477). Additionally, libraries of fragments of the protein coding sequence can be used to generate a diversified population of fragments for screening and subsequent selection of variants of a protein of the invention. In one embodiment, a library of coding sequence fragments can be generated by treating a double-stranded PCR fragment of a coding sequence of the invention with a nuclease under conditions in which nick occurs approximately once per molecule, denaturation of double-stranded DNA , renaturation of the DNA to form double-stranded DNA which may include sense / antisense pairs from different nicked products, elimination of monocatenary portions from reformed duplexes by treatment with nuclease SI and ligation of the resulting fragment library to a expression vector. By said method, an expression library encoding N-terminal and internal fragments of various sizes of the protein of the invention can be derived. Various methods are known in the art for the screening of gene products from combinatorial libraries produced by point mutations or truncation and for the screening of cDNA libraries for gene products having a selected property. Said methods are adaptable for rapid screening of the gene libraries generated by the combinatorial mutagenesis of the protein of the invention. The most widely used methods that are suitable for high capacity analysis for the screening of large gene libraries typically include cloning of the gene library into replicable expression vectors, transformation of appropriate cells with the resulting vector library, and expression of the combinatorial genes in conditions in which the detection of a desired activity facilitates the isolation of the vector encoding the gene whose product has been detected. Joint recursive mutagenesis (REM), a technique that improves the frequency of functional mutants in libraries, can be used in combination with screening assays to identify variant proteins of the invention (Arkin et al., Proc Nati Acad Sci USA (1992), 89: 7811-7815, Delgrave et al., Protein Engineering (1993) 6 (3): 327-331). Analogs and Derivatives of the Invention Protein Additionally, the present invention also includes derivatives or analogs of the protein of the invention produced by a chemical modification. A protein of the present invention can be derivatized by the attachment of one or more chemical moieties to the rest of the protein. Chemical moieties suitable for derivatization can be selected from water-soluble polymers so that the analog or derivative does not precipitate in an aqueous environment, such as a physiological environment. Optionally, the polymer will be pharmaceutically acceptable. One skilled in the art will be able to select the desired polymer on the basis of considerations such as whether the polymer / component conjugate is used therapeutically, and in such a case, the desired dosage, the circulation , the resistance to proteolysis, and Other considerations. For the protein of the invention, these can be ascertained using the assays provided herein. Examples of water-soluble polymers having applications in this invention include, but are not limited to, polyethylene glycol, ethylene glycol / propylene glycol copolymers, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1,3-dioxolane, poly - 1,3, 6-trioxane, ethylene / maleic anhydride copolymer, polyamino acids (whether homopolymers or random copolymers), dextran, poly (-vinyl-pyrrolidone) -polyethylene glycol, polypropylene glycol homopolymers, poly (propylene oxide / oxide) copolymers of ethylene), polyoxyethylated polyols or poly (vinyl alcohol). The propionic polyethylene glycol aldehyde may have advantages in manufacturing due to its stability in water. The polymer can be of any molecular weight, and can be branched or free of ramifications. In the case of polyethylene glycol, the preferred molecular weight is between approximately 2 KDa and approximately 100 KDa (indicating the term "approximately" that in polyethylene glycol preparations, some molecules will weigh more, and some less, than the indicated molecular weight) for ease in handling and manufacturing. Other sizes may be used, depending on the desired therapeutic profile (eg, the duration of the desired sustained release, the effects, if any, on biological activity, ease of handling, degree or lack of antigenicity, and other known effects of the polyethylene- • glycol pHHiffii • nadfir (DD spml1a®ra ^ |) thammersin sJailed to the protein of the invention may vary, and one skilled in the art will be able to ascertain the effect on the function.It is possible to mono-derivatize , or provide a combination of di-, tri-, tetra- or any other combination of derivatization, with the same or different chemical moieties (eg, polymers, such as different polyethylene glycol weights) .The ratio of polymer molecules to protein molecules of the invention will vary, as will their concentrations in the reaction mixture.In general, the optimum ratio (in terms of reaction efficiency in the sense that no there is any excess of component or components and unreacted polymer) will be determined by factors such as the degree of derivatization desired (v. g. , mono-, di-, tri-, etc.), the molecular weight of the selected polymer, if the polymer is branched or free of branching, and the reaction conditions. The polyethylene glycol molecules (or other chemical moieties) should be fixed to the protein of the invention with consideration of the effects on the functional or antigenic domains. There are a number of attachment methods available to those skilled in the art, eg, as indicated in EP 0401384 incorporated herein by reference (coupling of PEG to G-CSF), see also Malik et al., 1992, Exp. Hematol. 20: 1028-1035 (which lists the binding of PEG to GM-CSF using tresyl chloride). For example, polyethylene glycol can be covalently linked through amino acid residues via a reactive group, such as a free amino or carboxyl group. Reactive groups are those to which an activated polyethylene glycol molecule can be attached. The amino acid residues that have a free amino group include lysine residues and the N-terminal amino acid residues; those having a free carboxyl group include aspartic acid residues, glutamic acid residues, and the residue of a C-terminal amino acid. Sulfhydryl groups can also be used as a reactive group for fixing the polyethylene glycol (s). For therapeutic purposes, attachment to an amino group, such as fixation at the N-terminus or lysine group, is preferred. It is possible to specifically desire a chemically modified protein at the N-terminus of the invention. By using polyethylene glycol as an illustration of the present compositions, it is possible to select from a variety of polyethylene glycol molecules (by molecular weight, branching, etc.), the ratio of polyethylene glycol molecules to protein molecules of the invention in the mixture of polyethylene glycol. reaction, the type of PEG binding reaction to be performed, and the method of obtaining the selected molecule fixed to PEG in the N-terminal position. The method of obtaining the N-terminally pegylated preparation (ie the separation of this residue from other monopegylated moieties if necessary) can be by purification of the N-terminally pegylated material from a population of pegylated protein molecules. . Selective N-terminal chemical modification can be performed by reductive alkylation which exploits the differential reactivity of different types of primary amino groups (lysine versus N-terminal) available for derivatization. Under the appropriate reaction conditions, a substantially selective derivatization is achieved at the N-terminus with a carbonyl group-containing polymer. For example, it is possible to selectively pegilate the protein of the invention N-terminally by carrying out the reaction at a pH which makes it possible to take advantage of the pKa differences between the e-amino groups of the lysine residues and that of the group a -amino of the N-terminal residue. By such selective derivatization, the binding of a water-soluble polymer to the protein of the invention is controlled: the conjugation with the polymer takes place predominantly at the N-terminus and no significant modification of other reactive groups occurs, such as the amino groups of the side chain lysine. Using reductive alkylation, the water soluble polymer may be of the type described above, and should have a single reactive aldehyde for coupling to the protein of the invention. Polyethylene glycol-propionic aldehyde, which contains a single reactive aldehyde, can be used. Antibodies An isolated protein of the invention or a portion or fragment thereof can be used as an immunogen to generate antibodies that bind the protein of the invention using standard techniques for preparation of polyclonal and monoclonal antibodies. The term "antibody", as used herein, refers to immunoglobulin molecules and immunologically active portions of immunoglobulin molecules, i.e., molecules that contain an antigen binding site that is specific for - ie , which binds to an antigen, such as the protein of the invention, or a fragment thereof. A molecule that binds specifically to the protein of the invention is a molecule that binds the protein of the invention, but does not substantially fix other molecules contained in a sample, e.g., a biological sample that naturally contains the protein of the invention. Examples of immunologically active portions of immunoglobulin molecules include fragments F ^) and F (at, ') 2 that can be generated by treatment of the antibody with an enzyme such as pepsin. The invention provides polyclonal, monoclonal and chimeric antibodies that contain the protein of the invention, a variant thereof, a fragment thereof, or an analogue or derivative thereof, such as an immunogen. Chimeric antibodies are preferred for use in the therapy of human diseases or disorders, since human or humanized antibodies are much less likely than xenogenic antibodies to induce an immune response, in particular an allergic response. The full-length protein of the invention can be used or, alternatively, the invention provides fragments of antigenic peptides of the invention for use as immunogens. The antigenic peptide of the invention comprises at least 8 (preferably 10, 15, 20, 30 or more) amino acid residues of the amino acid sequence shown in SEQ ID No: 2 and encompasses an epitope such that an antibody-generated against the peptide forms a specific immunological complex with the protein of the invention. An immunogen is typically used to prepare antibodies by immunization of a suitable individual (e.g., rabbit, goat, mouse or other mammal) with the immunogen. An appropriate immunogenic preparation may contain, for example, the recombinantly expressed protein of the invention or a polypeptide of the invention chemically synthesized. The preparation may additionally include an adjuvant, such as complete or incomplete Freund's adjuvant or a similar immunostimulating agent. Immunization of a suitable individual with an immunogenic preparation induces a polyclonal antibody response directed against the protein of the invention. An antibody of the present invention can be a monoclonal antibody, a polyclonal antibody, or a chimeric antibody. The term "monoclonal antibody" or "monoclonal antibody composition", as used herein, refers to a population of antibody molecules that contain a single species of an antigen binding site capable of immunologically reacting with an epitope. particular of the protein of the invention. A monoclonal antibody composition thus typically exhibits a simple binding affinity for a particular epitope of the protein of the invention. Polyclonal antibodies can be prepared as described above by immunization of a suitable individual with an immunogen of the invention. The antibody titer in the immunized individual can be monitored over time by standard techniques, for example with an enzyme-linked immunosorbent assay (ELISA) using the protein of the invention that has been immobilized. If desired, the antibody molecules directed against the protein of the invention can be isolated from the mammal (e.g., from the blood) and further purified by well known techniques, such as protein A chromatography to obtain the IgG fraction. After an appropriate time after the immunization, e.g. , when antibody titres are maximal, antibody producing cells can be obtained from the individual and used to prepare monoclonal antibodies by standard techniques, such as the hybridoma technique originally described by Kohier et al., Nature (1975) 256: 495-497 , the hybridoma technique of human B cells (Kohier et al., Immunol Today (1983) 4: 72), the EBV hybridoma technique (Colé et al., Monoclonal Antibodies and Cancer Therapy (1985), Alan R. Liss Inc., pp. 77-96) or trioma techniques. The technology for the production of hybridomas is well known (see generally Current Protocols in Immunology (1994) Coligan et al., Compilers, John Wiley & amp;; Sons, Inc., New York, NY). Briefly, an immortal cell line (typically a myeloma) is fused to lymphocytes (typically splenocytes) of a mammal immunized with an immunogen of the invention as described above and the culture supernatants of the resulting hybridoma cells are screened to identify a hybridoma that produces a monoclonal antibody that binds to the protein of the invention. Any of the many well-known protocols used for the fusion of lymphocytes and immortalized cell lines can be applied for the purpose of generating a monoclonal antibody (see, eg, Current Protocols in Immunology, supra, Galfre et al., Nature (1977) 266 : 550-552, Kenneth, in Monoclonal Antibodies: A New Dimension in Biological Analyzes, Plenum Publishing Corp., New York, NY (1980), and Lerner, Yale J Biol Med (1981) 54: 387-402). In addition, the technician with ordinary experience will appreciate that there are many variations of such methods that could be useful as well. Typically, the immortal cell line (e.g., a myeloma cell line) is derived from the same mammalian species as the lymphocytes. For example, murine hybridomas can be produced by lymphocyte fusion of a mouse immunized with an immunogenic preparation of the present invention with a line of immortalized mouse cells, eg, a myeloma cell line that is sensitive to a culture medium containing hypoxanthine, aminopterin and thymidine ("HAT medium"). Any of numerous myeloma cell lines can be used as a fusion partner according to standard techniques, eg, myeloma lines P3-NS1 / I-AG4-1, P3-x63-Ag8.653 or Sp2 / 0-AgI4 . Myeloma lines are available from ATCC. Typically, HAT-sensitive mouse myeloma cells are fused to mouse splenocytes using polyethylene glycol ("PEG"). The hybridoma cells resulting from the fusion are then selected using HAT medium which destroys the unfused and unproductively fused myeloma cells (the unfused splenocytes die after several days because they are not transformed). Hybridoma cells producing a monoclonal antibody of the invention are detected by screening the culture supernatants of the hybridoma for antibodies that bind the protein of the invention, e.g. using a standard ELISA assay. As an alternative to the preparation of monoclonal antibody secretion hybridomas, a monoclonal antibody can be identified and isolated by screening a combinatorial recombinant immunoglobulin library (eg, a phage display antibody library) with the protein of the invention to isolate This mode members of the immunoglobulin library that bind the protein of the invention. Cassettes for generation and screening of phage display libraries are commercially available (e.g., Pharmacia Recombinant Phage Antibody System, Catalog No. 27-9400-01, and Stratagene "SURFZAP" Phage Display Kit, Catalog No. 240612). Additionally, examples of methods and reagents particularly suitable for use in the generation and screening of presentation antibody libraries are known to those skilled in the art (eg, Fuchs et al., Bio / Technology (1991) 9: 1370- 1372; Hay et al., Hum Antibody Hybridomas (1992) 3: 81-85, Huse et al., Science (1989) 246: 1275-1281, Griffiths et al., EMBO J. (1993) 25 (12): 725-734; US Patent No. 5,223,409; PCT Publication No. WO 92/18619; PCT Publication No. WO 91/17271; PCT Publication No. WO 92/20791; PCT Publication No. WO 92/15679; PCT Publication; No. WO 93/01288; PCT Publication No. WO 92/01047; PCT Publication No. WO 92/09690; PCT Publication No. WO 90/02809, the disclosures of which are incorporated by reference). Additionally, recombinant antibodies such as chimeric and humanized monoclonal antibodies comprising both human and non-human portions can be produced using standard recombinant DNA techniques. Such chimeric and humanized monoclonal antibodies can be produced by recombinant DNA methods known in the art (for example using methods described in PCT Publication No. WO 87/02671).; European Patent Application No. 184,187; European Patent Application No. 171,496; European Patent Application No. 173,494; PCT Publication No. WO 86/01533; U.S. Patent No. 4,816,567; European Patent Application No. 125,023; Better et al., Science (1988) 240: 1041-1043; Liu et al., Proc Nati Acad Sci USA (1987) 84: 3439-3443; Lin et al., J. Immunol. (1987) 139: 3521-3526; Sun et al., Proc Nati Acad Sci USA (1987) 84: 214-218; Nishimura et al., Canc Res (1987) 47: 999-1005; Wood et al., Nature (1985) 314: 446-449; Shaw et al., J. Nati Cancer Inst (1988) 80: 1553-1559; Morrison, Science (1985) 229: 1202-1207; Oi et al., Bio / Techniques (1986) 4: 214; U.S. Patent No. 5,225,539; Jones et al., Nature (1986) 321: 522-525; Verhoeyan et al., Science (1988) 239: 1534; and Beidler et al. J Immunol (1988) 141: 4053-4060, the descriptions of which are incorporated by reference). Fully human antibodies are particularly desirable for therapeutic treatment of human patients. Such antibodies can be produced using transgenic mice that are unable to express endogenous immunoglobulin heavy and light chain genes, but can express human heavy and light chain genes. The transgenic mice are immunized in the normal manner with a selected antigen, e.g., all or a portion of the protein of the invention. Monoclonal antibodies directed against the antigen can be obtained using conventional hybridoma technology. The human immunoglobulin transgenes harbored by the transgenic mice are rearranged during the differentiation of B cells and subsequently undergo class change and somatic mutation. Thus, using an epitope of this type, e.g., an antibody is identified that inhibits the activity of the protein of the invention. The heavy chain and light chain of the non-human antibody are cloned and used to create Fab fragments of phage display. For example, the heavy chain gene can be cloned into a plasmid vector such that the heavy chain can be secreted from bacteria. The light chain gene can be cloned to a gene of the phage coat protein such that the light chain can be expressed on the surface of the phage. A repertoire (random collection) of human light chains fused to phage is used to infect the bacteria expressing the non-human heavy chain. The phage of the resulting progeny exhibit hybrid antibodies (human light chain / non-human heavy chain). The selected antigen is used in a panning scrub to select the phage that binds the selected antigen. Several rounds of selection may be required to identify said phage. Selected human light chain genes that bind the selected antigen are isolated from the selected phage. The selected human light chain genes are then used to guide the selection of human heavy chain genes as follows. The selected human light chain genes are inserted into vectors for expression by bacteria. Bacteria expressing the selected human light chain are infected with a repertoire of human heavy chains fused to phage. The phage of the resulting progeny present human antibodies (human light chain / human heavy chain). Next, the selected antigen is used in a panning scrutiny to select phages that bind the selected antigen. The selected phages display a fully human antibody that recognizes the same epitope recognized by the original non-human monoclonal antibody selected. The genes encoding both the heavy and light chains are isolated and can be further manipulated for human antibody production. The technology has been described by Jespers et al. (Bio / Technology (1994) 12: 899-903). An antibody (e.g., a monoclonal antibody) can be used to isolate the protein of the invention by standard techniques, such as affinity chromatography or immunoprecipitation. An antibody directed against the protein of the invention can facilitate the purification of the native protein from cells and the recombinantly produced protein in host cells. In addition, an antibody can be used to detect the protein of the invention (e.g., in a cell lysate or supernatant of cells) in order to evaluate the abundance and the expression pattern of the protein. Antibodies can be used diagnostically to observe protein levels in tissues as part of a clinical assay procedure, for example, to determine the efficacy of a given treatment regimen. Detection can be facilitated by coupling the antibody to a detectable substance, which is described below. Detectable Markers Optionally, the isolated nucleic acid molecules of the present invention, polypeptides of the present invention, and antibodies of the present invention, as well as fragments of such moieties, can be detectably labeled. Suitable labels include enzymes, fluorophores (eg, fluorescein isothiocyanate (FITC), phycoerythrin (PE), Texas red (TR), rhodamine, salts of the free lanthanide series or forming chelates, especially Eu3 +, to name a few fluorophores ), chromophores, radioisotopes, chelating agents, dyes, colloidal gold, latex particles, ligands (eg, biotin), bioluminescent materials, and chemiluminescent agents. When a control marker is employed, the same or different tracers may be used for the receiver and the control marker. In the case where a radioactive tracer is used, such as the isotopes 3H, 14C, 32P, 35S, 3SC1, 51Cr, 57Co, 58Co, 59Fe, 90Y, 125I, 131I, and a8SRe, known counting procedures commonly available can be employed. . In the case where the tracer is an enzyme, the detection can be performed by any of the colorimetric, spectrophotometric, fluorospectrophotometric, amperometric or gasometric methods known in the art and currently used. The direct tracers are an example of detectable tracers that can be used in accordance with the present invention. A direct tracer has been defined as an entity which, in its natural state, is easily visible, either to the naked eye, or with the aid of an applied optical filter and / or stimulation, e.g., U.V. to promote fluorescence. Examples of colored tracers that can be used in accordance with the present invention include metal sol particles, for example gold sol particles such as those described by Leuvering (U.S. Patent No. 4,313,774); colorant sol particles such as those described by Gribnau et al. (U.S. Patent No. 4,373,932) and May et al. (WO 88/08534); dyed latex such as that described by May, supra, Snyder (EP-A 0 280 559 and 0 281 327), or colorants encapsulated in liposomes as described by Campbell et al. (U.S. Patent 4,703,017). Other direct tracers include a radionucleotide, a fluorescent moiety or a luminescent moiety. In addition to these direct tracer devices, indirect tracers comprising enzymes according to the present invention can also be used. Various types of enzyme-linked immunoassays are well known in the art, for example, alkaline phosphatase and horseradish peroxidase, lysozyme, glucose-6-phosphate dehydrogenase, lactate dehydrogenase, urease, these and others have been discussed in detail by Eva Engvall in Enzyme Immunoasay ELISA and EMIT in Methods in Enzymology, 70, 419-439, 1980 and in US Pat. 4,857,453. Other detectable tracers for use in the invention include magnetic beads or magnetic resonance imaging tracers. In another embodiment, a phosphorylation site can be created in an isolated polypeptide of the present invention, an antibody of the present invention, or a fragment thereof, for 32 P, v. Labeling. g. , as described in European Patent No. 0372707. As illustrated herein, proteins, including antibodies, can be detectably labeled by metabolic labeling. Metabolic labeling occurs during in vitro incubation of cells expressing the protein in the presence of a culture medium supplemented with a metabolic tracer, such as [35 S] -methionine or [32 P] -ortophosphate. In addition to metabolic or biosynthetic labeling with [35 S] -methionine, the invention additionally contemplates labeling with [14 C] -amino acids and [3 H] -amino acids (with substituted tritium at non-labile positions). The antibodies can be further detected using, in addition to the tracer cited above, antigenic peptide labels recognizable by antibodies. Examples include HA tags and FLAG tags. Recombinant Expression Vectors and Host Cells Another aspect of the invention relates to vectors, preferably expression vectors, that contain a nucleic acid encoding SEQ ID NO: 1 or a portion thereof. As explained above, one type of vector is a "plasmid", a term that refers to a circular double-stranded DNA loop to which additional DNA segments can be ligated. Another type of vector is a viral vector, in which case additional DNA segments can be ligated to a viral genome. Certain vectors are capable of autonomous replication in a host cell (e.g., bacterial vectors having a bacterial origin of replication and mammalian episomal vectors). Other vectors (e.g., non-episomal mammalian vectors) are integrated into the genome of a host cell by introduction into the host cell and replicated by. both together with the host's genome. In addition, expression vectors are capable of directing the expression of genes operably linked to them. In general, expression vectors of utility in recombinant DNA techniques are often found in the form of plasmids (vectors). However, the invention is intended to include such other forms of expression vectors, such as viral vectors (e.g., replication-deficient retroviruses, adenoviruses and adeno-associated viruses), which serve equivalent functions. A recombinant expression vector of the invention comprises a nucleic acid molecule of the present invention in a form suitable for the expression of the nucleic acid in a host cell. This means that a recombinant expression vector of the present invention includes one or more regulatory sequences, selected on the basis of the host cells to be used for the expression, which is operatively linked to the nucleic acid to be expressed. Within a recombinant expression vector, the term "operably linked" is intended to mean that the nucleotide sequence of interest is linked to the regulatory sequence (s) in a manner that allows expression of the nucleotide sequence (eg, in a of transcription / translation in vi tro or in a host cell when the vector is introduced into the host cell). The term "regulatory sequence" is intended to include promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Such regulatory sequences are described, for example, in Goeddel, Gene Expression Technology: Methods in Enzymology Vol. 185, Academic Press, San Diego, Ca (1990). Regulatory sequences include those that direct the constitutive expression of the nucleotide sequence in many types of host cells (e.g., tissue-specific regulatory sequences). It will be appreciated by those skilled in the art that the design of the expression vector may depend on factors such as the choice of the host cell to be transformed, the level of protein expression desired, etc. The expression vectors of the invention can be introduced into host cells to produce proteins or peptides encoded by nucleic acids as described herein. A recombinant expression vector of the invention can be designed for the expression of SEQ ID NO: 1 or a portion thereof in prokaryotic or eukaryotic cells, e.g., bacterial cells such as E. coli, insect cells. (using baculovirus expression vectors), yeast cells or mammalian cells. Suitable host cells are further discussed in Goeddel, supra. Alternatively, the recombinant expression vector can be transcribed and translated in vi tro, for example using phage regulatory elements and proteins, such as a T7 promoter and / or a T7 polymerase. The expression of proteins in prokaryotes is carried out in most cases in E. coli with vectors containing constitutive or inducible promoters that direct the expression of proteins, whether or not they are fusion proteins. The fusion vectors add a certain number of amino acids to a protein encoded therein, usually to the amino terminus of the recombinant protein. Such fusion vectors typically serve three purposes: 1) increase the expression of recombinant protein; 2) increase the solubility of the recombinant protein; and 3) facilitate the purification of the recombinant protein by acting as a ligand in the affinity purification. Often, in fusion expression vectors, a proteolytic cleavage site is introduced at the junction of the fusion moiety and the recombinant protein to allow separation of the recombinant protein from the fusion moiety subsequent to the purification of the protein. of fusion. Such enzymes and related recognition sequences include Factor Xa, thrombin and enterokinase. Typical fusion expression vectors include pGEX (Pharmacia Biotech Inc., Smith et al., Gene (1988) 67: 31-40), pMAL (New England Biolabs, Beverly, M?) And pRITS (Pharmacia, Piscataway, NJ) , which fuse glutathione-5-transferase (GST), the E-binding protein of maltose or protein A, respectively, to the target recombinant protein. Examples of suitable non-fusion inducible E. coli expression vectors include pTrc (Amann et al., Gene (1988) 69: 301-315) and pET lid (Studier et al., Gene Expression Technology: Methods in Enzymology , Academic Press, San Diego, California (1990) 185: 60-89). The expression of the target gene by the pTrc vector is based on the transcription by the RNA polymerase of the host of a trp-lac hybrid fusion promoter. One strategy to maximize expression of recombinant proteins in E. coli is to express the protein in a host that has impaired ability to proteolytically cleave the recombinant protein (Gottes-man, Gene Expression Technology: Methods in Enzymology, Academic Press, San Diego, California (1990) 185: 119-128). Another strategy is to alter the nucleic acid sequence of the nucleic acid molecule to be inserted into an expression vector such that the individual codons for each amino acid are those preferably used in E. coli (Wada et al., Nucleic Acids Res. (1992) 20: 2111-2118). Said alteration of nucleic acid sequences of the invention can be carried out by standard methods of DNA synthesis. In another embodiment, the expression vector of the invention is a yeast expression vector. Examples of vectors for expression in yeast such as S. cerevisiae include pYepSecl (Baldari et al., EMBO J (1987) 6: 229-234), pMFa (Kurjan et al., Cell (1982) 30: 933-943) , pJRY88 (Schultz et al., Gene (1987) 54: 113-123), pYES2 (Invitrogen Corporation, San Diego, CA) and pPicZ (Invitrogen Corp. San Diego, CA). Alternatively, SEQ ID NO: 1 or a portion thereof can be expressed in insect cells using vectors of baculovirus expression. Baculovirus vectors available for expression of proteins in cultured insect cells (eg Sf 9 cells) include the pAc series (Smith et al., Mol Cell Biol (1983) 3: 2156-2165 and the pVL series (Lucklow et al. , Virology (1989) 170: 31-39) In a further embodiment, a nucleic acid of the invention is expressed in mammalian cells using a mammalian expression vector Examples of mammalian expression vectors having applications in this memory include, but certainly not limiting, pCDM8 (Seed, Nature (1987) 329: 840) and pMT2PC (Kaufman et al., EMBO J (1987) 6: 187-195). When used in mammalian cells, the control functions of the expression vector are often provided by viral regulatory elements. For example, commonly used promoters are derived from polyoma, adenovirus 2, cytomegalovirus and simian virus 40. For other expression systems suitable for both prokaryotic and eukaryotic cells, see chapters 16 and 17 of Sambrook et al. , supra. In another embodiment, a mammalian recombinant expression vector of the present invention is capable of directing the expression of the nucleic acid preferentially in a particular cell type (e.g., tissue-specific regulatory elements are used to express the nucleic acid). Specific regulatory elements of tissues are known in the art. Non-limiting examples of suitable tissue-specific promoters include the albumin promoter (liver specific; Pinkert et al., Genes Dev (1987) 1: 268-277), specific lymphoid promoters (Caiame et al., Adv Immunol (1988) 43: 235-275), in particular, promoters of T cell receptors (Winoto et al. al., EMBO J (1989) 8: 729-733) and immunoglobulins (Banerj i et al., Cell (1983) 33: 729-740; Queen et al., Cell (1983) 33: 741-748), producers neuron-specific promoters (eg the neurofilament promoter; Byrne et al., Proc Nati Acad Sci USA (1989) 86: 5473-5477), pancreas-specific promoters (Edlund et al., Science (1985) 230: 912-916) and mammary gland specific promoters (eg, whey promoter, US Patent No. 4,873,316 and European Application No. 264,166). Experimentally regulated promoters are also contemplated, for example the murine hox promoters (Kessel et al., Science (1990) 249: 374-379) and the α-fetoprotein promoter (Campes et al., Genes Dev (1989) 3). : 537-546). The descriptions of each of the foregoing citations are incorporated herein by reference. The invention further provides a recombinant expression vector comprising a DNA molecule of the invention cloned into an expression vector in antisense orientation. Namely, the DNA molecule is operably linked to a regulatory sequence in a manner that allows the expression (by transcription of the DNA molecule) of an RNA molecule that is antisense to the mRNA of the invention. Regulatory sequences operably linked to a nucleic acid cloned in the antisense orientation can be selected, which direct the continuous expression of the antisense RNA molecule in a variety of cell types. For example, promoters and / or viral enhancers or regulatory sequences that direct the expression of constitutive, tissue-specific or cell-type antisense RNA can be selected. The antisense expression vector can be found in the form of a recombinant plasmid, phagemid or attenuated virus in which antisense nucleic acids are produced under the control of a high efficiency regulatory region, whose activity can be determined by the type of antisense nucleic acid. cell in which the vector is introduced. For an exposition of the regulation of gene expression using antisense genes, see Weintraub et al. (Reviews- Trends in Genetics, Vol. 1 (1) 1986). Another aspect of the present invention relates to host cells in which a recombinant expression vector of the invention has been introduced. The terms "host cell" and "recombinant host cell" are used interchangeably herein. It should be understood that these terms refer not only to the particular target cell but also to the progeny or potential progeny of such a cell. Because certain modifications may occur in succeeding generations due to mutation or environmental influences, said progeny may, in fact, not be identical to the parent cell, but is still included within the scope of the term as used herein. A host cell can be any prokaryotic or eukaryotic cell. For example, the protein of the invention can be expressed in bacterial cells such as E. coli, insect cells, yeast or mammalian cells (such as Chinese hamster ovary (CHO) cells, 293 cells or COS cells). Other suitable host cells are known to those skilled in the art. The vector DNA can be introduced into prokaryotic or eukaryotic cells by conventional methods of transformation or transfection. As used herein, the terms "transformation" and "transfection" are intended to refer to a variety of methods recognized in the art for introducing foreign nucleic acid (eg, DNA) into a host cell, including coprecipitation with calcium phosphate or calcium chloride, transduction, transfection mediated by DEAE-dextran, lipofection or electroporation. For stable transfection of mammalian cells, it is known that, depending on the expression vector and the transfection method used, only a small fraction of cells can integrate the foreign DNA into the genome. To identify and select the members, a gene encoding a selectable marker (e.g., for resistance to antibiotics) is generally introduced into the host cells together with the gene of interest. Preferred selectable markers include those that confer resistance to drugs, such as G418, hygromycin and methotrexate. A nucleic acid encoding a selectable marker can be introduced into a host cell in the same vector as that encoding SEQ ID NO: 1 or a portion thereof, or the nucleic acid encoding a selectable marker can be introduced into a vector separated. For example, cells stably transfected with the introduced nucleic acid can be identified by drug selection (e.g., cells that have the selectable marker gene incorporated will survive, while the other cells will die). A host cell of the invention, such as a prokaryotic or eukaryotic host cell in culture, can be used to produce (ie, express) the protein of the invention. Accordingly, the invention further provides methods for producing SEQ ID NO: 2 or a portion thereof by utilization of the host cells of the invention. In one embodiment, the method comprises culturing the host cell of the invention (into which a recombinant expression vector encoding SEQ ID NO: 1) has been introduced in a suitable medium such that the protein of the invention is produced. In another embodiment, the method further comprises isolating the protein of the invention from the host cell or medium. In another embodiment, the invention comprises an inducible expression system for the recombinant expression of other proteins subcloned in modified expression vectors. For example, host cells comprising a mutated G protein (e.g., yeast cells, adrenocortical cells Y2 and cyc ~ S49, see U.S. Patent Nos. 6,168,927 Bl, 5,739,029 and 5,482,835.; Mitchell et al., Proc Nati Acad Sci USA (1992) 89 (19): 8933-37 and Katada et al., J Biol Chem (1984) 259 (6): 3586-95) undergo transduction with a first vector of expression comprising a nucleic acid sequence encoding SEQ ID NO: 1, in which SEQ ID NO: 2 is functionally expressed in the host cells. Even when the expressed protein of the invention is constitutively active, the mutation does not allow signal transduction; that is, no activation of a downstream G-protein directed cascade occurs (e.g., there is no activation by adenylyl cyclase). Subsequently, a second expression vector is used to transduce the host cells comprising SEQ ID NO: 1. The second vector comprises a structural gene that complements the G protein mutation of the host cell (i.e., Gs, Gi, GQ or mammalian or yeast functional Gqs, eg see PCT Publication No. WO 97/48820, and US Patent Nos. 6,168,927 Bl, 5,739,029 and 5,482,835 and which are hereby incorporated by reference into US Pat. this memory in its totalities) besides the gene of interest to be expressed by the inducible system. The complementary structural gene of the second vector is inducible; that is, under the control of an exogenously added component (e.g., tetracycline, IPTG, small molecules, etc., see Sambrook et al., supra) that activates a promoter that is operably linked to the complementary structural gene. Once the inducer is added, the protein encoded by the complementary structural gene is functionally expressed in such a way that the constitutively active protein of the invention will now form a complex which leads to the activation of the appropriate path downstream (eg, formation of second messenger) . The gene of interest comprising the second vector possesses an operably linked promoter that is activated by the appropriate second messenger (e.g., CREB elements, API). Thus, as the second messenger accumulates, the promoter located upstream of the gene of interest is activated to express the product of said gene. When the inducer is absent, the expression of the gene of interest stops. In a particular embodiment, the host cells for the inducible expression system include, but are not limited to, S49 cells (cyc-). While cell lines comprising mutations of G proteins are contemplated, suitable mutants can be artificially produced / constructed (see U.S. Patent Nos. 6,168,927 Bl, 5,739,029 and 5,482,835 for yeast cells). In a related aspect, the cells are transfected with a vector operatively linked to a cDNA comprising a sequence encoding a protein as represented in SEQ ID NO: 2. The first and second vectors comprising said system are contemplated, but include without limitation, pCDM8 (Seed, Nature (1987) 329: 840) and pMT2PC (Kaufman et al., EMBO J (1987) 6: 187-195), pYepSecl (Baldari et al., EMBO J (1987) 6: 229-234), pMFa (Kurjan et al., Cell (1982) 30: 933-943), pJRY88 (Schultz et al., Gene (1987) 54: 113-123), pYES2 (Invitrogen Corporation, San Diego , CA) and pPicZ (Invitrogen Corp, San Diego, CA). In a related aspect, the host cells can be transfected by said suitable means, in which transfection results in the expression of a functional protein (eg, Sambrook et al., Supra, and Kriegler, Gene Transfer and Expression: A Laboratory Manual , Stockton PreSs, New York, NY, 1990). Such "functional proteins" include, but are not limited to, proteins that once expressed form complexes with G proteins, where the G proteins regulate the formation of the second messenger. Other methods for transfection of host cells having applications in this invention include, but are certainly not limiting, transfection, electroporation, microinjection, transduction, cell fusion, DEAE-dextran, calcium phosphate precipitation, lipofection (fusion of lysosomes), from a gene gun, or a DNA vector transporter (see, eg, Wu et al., 1992, J. Biol. Chem. 267: 963-967; Wu and Wu, 1988, J. Biol. Chem. 263: 14621-14624; Hartmut et al., Canadian Patent Application No. 2,012,311, filed March 15, 1990). A wide variety of promoters have applications in the present invention. In fact, the expression of a polypeptide of the present invention can be controlled by any promoter / enhancer element known in the art, but these regulatory elements have to be functional in the host selected for expression. Promoters that can be used to control expression include, but are not limited to, the early promoter region of SV40 (Benoist and Chambon, 1981, Nature 290: 304-310), the promoter contained in the repeat of the long terminal 3 'of the virus of the Rous's sarcoma (Yamamoto, et al., 1980, Cell 22: 787-797), the herpes thymidine kinase promoter, Wagner et al., 1981, Proc Nati Acad Sci USA 78: 1441-1445), the sequences regulators of the metallothionein gene (Brinster et al., 1982, Nature 296: 39-42); prokaryotic expression vectors such as the / 3-lactamase promoter (Villa-Kamaroff et al., 1978, Proc Nati Acad Sci USA 75: 3727-3731), or the tac promoter (DeBoer, et al., 1983, Proc Nati Acad Sci USA 80: 21-25); see also "Useful proteins from recombinant bacteria" in Scientific American, 1980, 242: 74-94, yeast or other fungal promoter elements such as the Gal 4 promoter, the ADC (alcohol dehydrogenase) promoter, the PGK (phospholipid) promoter. rol-kinase), the alkaline phosphatase promoter, - and the animal transcriptional control regions, which exhibit tissue specificity and have been used in transgenic animals: the control region of the elastase I gene that is active in cells pancreatic acinars (Swift et al., 1984, Cell 38: 639-646, Ornitz et al., 1986, Cold Spring Harbor Symp Quant Biol 50: 399-409, McDonald, 1987, Hepatology 7: 425-515); the control region of the insulin gene that is active in pancreatic beta cells (Hanahan, 1985, Nature 315: 115-122, the control region of the immunoglobulin gene that is active in lymphoid cells (Grosschedl et al., 1984 , Cell 38: 647-658; Adames et al., 1985, Nature 318: 533-538; Alexander et al., 1987, Mol Cell. Biol. 7: 1476-1444), the control region of the tumor virus mammary of the mouse that is active in testi-cular, breast, lymphoid and mast cells (Leder et al., 1986, Cell 45: 485-495, the control region of the albumin gene that is active in the liver (Pinkert et al. al., 1987, Genes and Devel 1: 268-276), the control region of the alpha-fetoprotein gene that is activated in the liver (Krumlauf et al., 1985, Mol. Cell. Biol. 5: 1639-1648 Hammer et al., 1987, Science 235: 53-58), the control region of the alpha-1 antitrypsin gene that is active in the liver (Kelsey et al., 1987, Genes and Devel. 1: 161-171 ), the control region of the / 3-globin gene which is active in myeloid cells (Mogram et al., 1985, Nature 315: 338-340; Kollias et al., 1986, Cell 46.-89-94), the control region of the myelin basic protein gene, which is active in the brain's oligodenocytes (Readhead et al., 1987, Cell 48: 703 - 712), the control region of the myosin light chain 2 gene that is active in the skeletal muscles (Sani, 1985, Nature 314: 283-286), and the control region of the gonadotropin-releasing hormone gene , which is active in the hypothalamus (Mason et al., 1986, Science 234: 1372-1378). Expression vectors containing a nucleic acid molecule of the invention can be identified by four general methods: (a) PCR amplification of the desired plasmid DNA or mRNA, (b) nucleic acid hybridization, (c) presence or absence of gene functions, selection markers, and (d) expression of inserted sequences. In the first method, the nucleic acids can be amplified by PCR to facilitate the detection of the amplified product. In the second method, the presence of a foreign gene inserted into an expression vector can be detected by nucleic acid hybridization using probes comprising sequences that are homologous to an inserted marker gene. In the third method, the recombinant / host vector system can be identified and selected based on the presence or absence of certain gene functions "selection markers" (eg, jß-galactosidase activity, thymidine kinase activity, antibiotic resistance, phenotype of transformation, formation of occlusion bodies in baculovirus, etc.) caused by the insertion of foreign genes in the vector. In another example, if the nucleic acid encoding the protein of the invention, a variant thereof, or an analog or derivative thereof, is inserted into the sequence of the "selection marker" gene of the vector, the recombinants that contain the insertion can be identified by the absence of the function of the gene. In the fourth method, the recombinant expression vectors can be identified by assay with respect to the activity, biochemical or immunological characteristics of the gene product expressed by the recombinant vector, provided that the expressed protein assumes a functionally active conformation. A great variety of host / expression vector combinations may be employed in the expression of the DNA sequences of this invention. Useful expression vectors may consist, for example, of segments of chromosomal, non-chromosomal and synthetic DNA sequences. Suitable vectors include known SV40 derivatives and bacterial plasmids, eg, the E.coli col El plasmids, pCRl, pBR322, pMal-C2, pET, pGEX (Smith et al., 1988, Gene 67: 31-40), pMB9 and its derivatives, plasmids such as RP4; Phage DNAs, e.g., the numerous phage derivatives?, E.g., NM989, and other phage DNAs, e.g. M13 and single stranded filamentous phage DNA; yeast plasmids such as 2μ plasmid or derivatives thereof, - vectors useful in eukaryotic strains, such as vectors useful in insect or mammalian cells; vectors derived from combinations of plasmids and phage DNAs, such as plasmids that have been modified to employ phage DNA or other expression control sequences; etc. For example, in a baculovirus expression system, both non-fusion transfer vectors may be used, such as, but not limited to, pVL941 (Ba Hl cloning site, Summers), pVL1393 (BairiHI cloning site, Smal , Xbal, EcoRI, Notl, XmalII, BglII, and PstI, Invitrogen), pVL1392 (cloning site BglII, PstI, Notl, ZmalII, EcoRI, Xbal, Smal, and BamHI, Summers and Invitrogen), and pBlueSacIII (cloning site Ba? RiH.1, BglII, PstI, EcoRI, and HindIII, with possible blue / white recombinant screening, Invitrogen), and transfer fusion vectors, such as, but not limited to, pAc700 (Bam cloning site? ly Kpnl, in which the BairiHI recognition site begins with the initiation codon, Summers), pAc701 and pAc702 (same as pAc700, with different reading frames), pAc360 (Ba? l cloning site, located 36 base pairs downstream of a polyhedrin initiation codon; ogen (195)), and pBlueBacHi-sA, B, C, (3 different reading frames, with cloning site BamHI, BgrlII, PstI, Ncol, and HindIII, a? -terminal peptide for ProBond purification, and plate screening recombinant blue / white, - Invitrogen (220). Mammalian expression vectors contemplated for use in the invention include vectors with inducible promoters, such as the dihydrofolate reductase (DHFR) promoter, e.g. , any expression vector with a DHFR expression vector, or a DHFR / methotrexate co-amplification vector, such as pED (PstI, SalI, Sbal, Smal and EcoR1 cloning site, the vector expressing both the cloned gene and DHFR; Kaufman, Current Protocols in Molecular Biology, 16.12 (1991), alternatively, a co-amplification vector glutamine synthetase / methionine sulfo-imine, such as pEE14 (HindIII cloning site, Xbal, Smal, Sbal, EcoRl, and Bell, in which the vector expresses glutamine synthase and the cloned gene; Celltech). In another embodiment, a vector that directs episomal expression under the control of Epstein Barr Virus (EBV), such as pREP4 (BairiKI cloning site, Sfil, Xhol, Notl, Nhel, HindIII, Nhel, Pvull, and Kpnl) can be used. , the constitutive promoter RSV-LTR, selectable marker of hygromycin, Invitrogen), pCEP4 (Barri? I cloning site, Sfil, Xhol, Notl, Nhel, HindIII, Nhel, PvulI, and Kpnl, immediate early gene constitutive of hCMV selectable hygromycin marker; Invitrogen), pMEP4 (Kpnl cloning site, Pvul, Nhel, HindIII, Notl, Xhol, Sfil, BamRl, the promoter of the inducible metallothionein gene, selectable hygromycin marker: Invitrogen), pREP8 (site of cloning BamHI, Xhol, Notl, HindIII, Nhel and Kpnl, promoter RSV-LTR, selectable marker of histidinol, InvProgen), pREP9 (cloning site Kpnl, Nhel, HindIII, Notl, Xhol, Sfil, and Ba HI, promoter RSV -LTR, selectable marker G418; Invitrogen), and pEBVHis (RSV-LTR promoter, labeled selectable hygromycin, N-terminal peptide purifiable by ProBond resin and cleaved by enterokinase, - Invitrogen). Selectable mammalian expression vectors for use in the invention include pRc / CMV (Hinldlll cloning site, BstXI, Notl, Sbal, and Apal, selection with G418, Invitrogen), pRc / RSV (HindIII cloning site, Spel, BstXI, Notl, Xfoal, selection with G418; Invitrogen), and others. Mammalian expression vectors of vaccinia virus (see, Kaufman, 1991, supra) for use in accordance with the invention include, but are not limited to, pSCll (Smal cloning site, selection by TK and / 3-gal), pMJ601 ( cloning site Salí, Smal, Afll, Narl, BspMll, Bamñl, Apal, Nhel, Sacll, Kpnl, and HindIII, selection by TK and? -gal), and pTKgptFIS (cloning site EcoRI, PstI, Salí, Accl, Hin -dll, Sbal, BamHI, and Hpa, selected by TK or XPRT). Yeast expression systems according to the invention can also be used to express the protein of the invention, a variant thereof, or an analogue or derivative thereof. For example, the non-fusion vector pYES2 (cloning site Xbal, Sphl, Shol, Notl, GstXl, EcoRl, BstXl, Bairi? L, Sacl, Kpnl and HipdlII; Invitrogen) or the fusion pYESHisA, B, C (site of cloning Xbal, Sphl, Shol, Notl, BstXl, EcoRl, Bam? l, Sacl, Kpnl and H ± ndIII, N-terminal peptide purified with ProBond resin and cleaved with enterokinase, Invitrogen), to mention only two, can be used according to the invention. Once a particular recombinant DNA molecule is identified and isolated, various methods known in the art can be used to propagate it. Once a suitable host system and culture conditions have been established, recombinant expression vectors can be propagated and prepared in quantity. As previously explained, expression vectors that can be used include, but are not limited to, the following vectors or their derivatives: human or animal viruses such as vaccinia virus or adenovirus; insect viruses such as baculovirus; yeast vectors, bacteriophage vectors (v. g., lambda), and plasmid and cosmid DNA vectors, to name but a few).

Additionally, a host cell strain that modulates the expression of the in-serted sequences, or modifies and processes the gene product in the specific manner desired, can be selected. Different host cells have characteristic and specific mechanisms for processing and modification in translation and post-translation (e.g., glycosylation, cleavage [e.g., of the signal sequence]) of the proteins. Appropriate cell lines or host systems can be selected to ensure the desired modification and processing of the expressed foreign protein. For example, expression in a bacterial system can be used to produce a non-glycosylated core protein product. Transgenic Animals A host cell of the present invention can also be used to produce transgenic non-human animals. For example, in one embodiment, a host cell of the invention is a fertilized oocyte or an embryonic stem cell in which sequences corresponding to SEQ ID NO: 1 have been introduced. Such host cells can then be used to create transgenic non-human animals in which the exogenous sequences have been introduced into the genome, or homologous recombinant animals in which endogenous sequences have been altered. Said animals are useful for studying the function and / or activity of the protein of the invention and for identifying and / or evaluating modulators of the activity of the protein of the invention. As used herein, a "transgenic animal" is a non-human animal, preferably a mammal, more preferably a rodent such as a rat or a mouse, in which one or more of the cells of the animal includes a transgene. Other examples of transgenic animals include non-human primates, sheep, dogs, cows, goats, chickens, amphibians, and the like. A particular embodiment of the invention is a guinea pig that over-expresses the receptor of the invention and could have utility as an animal model of allergic rhinitis, bronchial asthma or chronic obstructive pulmonary disease. As used herein, the term "transgene" refers to exogenous DNA that is integrated into the genome of a cell from which a transgenic animal develops and which remains in the mature animal's genome. The transgene directs the expression of a gene product encoded in one or more types of cells or tissues of the transgenic animal. As used herein, a "homologous recombinant animal" is a non-human animal, preferably a mammal, more preferably a mouse, in which an endogenous gene corresponding to SEQ ID NO: 1 has been altered by homologous recombination. This is performed between the endogenous gene and an exogenous DNA molecule introduced into an animal cell, e.g., an embryonic cell of the animal, prior to an animal's development. A transgenic animal of the invention can be created by introducing a nucleic acid molecule encoding SEQ ID NO: 1 or a portion thereof into the male pronuclei of a fertilized oocyte using one of the transfection methods described above. The oocyte is then allowed to develop in a pseudopregnant female adoptive animal. The cDNA sequence, e.g., that of (SEQ ID NO: 1), for example, can be introduced as a transgene in the genome of a non-human animal. Alternatively, a non-human homolog of the human gene, such as a mouse gene, can be isolated on the basis of hybridization to the cDNA corresponding to SEQ ID NO: 1, and used as a transgene. Intronic sequences and polyadenylation signals may also be included in the transgene to increase the efficiency of expression of the transgene. One or more tissue-specific regulatory sequences can be operably linked to the transgene of the invention to direct the expression of the protein of the invention in particular cells. Embodiments for the generation of transgenic animals via the manipulation and microinjection of embryos, particularly animals such as mice, are conventional in the art and are described, for example, in U.S. Pat. Núms. 4,736,866 and 4,870,009, U.S. Pat. No. 4,873,191 and in Hogan, Manipulating the Mouse Embryo (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. 1986), all of which descriptions are incorporated herein by reference. Similar methods are used for production of other transgenic animals with a transgene in the genome and / or expression of the mRNA of the invention in tissues or cells of animals. A founder transgenic animal can then be used to reproduce additional animals carrying the transgene. In addition, transgenic animals carrying a transgene encoding SEQ ID NO: 1 can reproduce further to produce other transgenic animals carrying other transgenes. To create a homologous recombinant animal, a vector is prepared that contains at least a portion of the gene of the invention (eg, a human or non-human homologue of the gene of the invention, eg, a murine gene) into which a deletion, addition or modification has been introduced. substitution to alter with it, vg functionally destroy the gene of the invention. In a particular embodiment, the vector is designed in such a way that, in homologous recombination, the endogenous gene is functionally destroyed (ie, it no longer encodes a functional protein; it is also referred to as a "knock out" vector). Alternatively, the vector can be designed such that, in homologous recombination, the endogenous gene undergoes a mutation or is altered in any other way but still encodes functional protein (eg, a regulatory region located upstream can be altered thereby altering the expression of the endogenous protein). In the homologous recombination vector, the altered portion of the gene is flanked at the 5 'and 3' ends by an additional nucleic acid sequence of the gene in order to allow homologous recombination to take place between the exogenous gene carried by the vector and an endogenous gene in an embryonic stem cell. The additional flanking nucleic acid sequence must be of sufficient length for satisfactory homologous recombination with the endogenous gene. Typically, several kilobases of flanking DNA (at both 5 'and 3' ends) are included in the vector (see, e.g., Thomas et al., Cell (1987) 51: 503 for a description of homologous recombination vectors). The vector is introduced into an embryonic stem cell line (eg, by electroporation) and cells are selected in which the introduced gene of the invention has been homologously recombined with the endogenous gene (see, eg, Li et al., Cell (1992) 69: 915). The selected cells are then injected into a blastocyst of an animal (eg, a mouse) to form aggregation chimeras (see, eg, Bradley in Teratocarcinomas and Embryo-nic Stem Cells: A Practical Approach, Robertson, Compiler, IRL, Oxford, (1987) pp. 113-152). A chimeric embryo may then be implanted in an appropriate pseudopregnant female adoptive animal and the embryo be completed. Progeny harboring the homologously recombined DNA in the germ cells can be used to reproduce animals in which all cells of the animal contain homologously recombined DNA by transmission of the germ line of the transgene. Methods for constructing homologous recombination vectors and homologous recombinant animals are further described in Bradley, Current Opinion in Bio / Technology (1991) 2: 823-829 and in PCT Publications Nos. WO 90/11354, WO 91/01140, WO 92/0968 and WO 93/04169, the descriptions of which are incorporated by reference. In another embodiment, transgenic non-human animals containing systems selected to allow regulated expression of the transgene can be produced. An example of such a system is the cre / loxP recombinase system of the bacteriophage Pl. For a description of the cre / loxP recombinase system, see, e.g., Lakso et al., Proc Nati Acad Sci USA (1992) 89: 6232-6236. Another example of a recombinase system is the FLP recombinase system of S. cerevisiae (O'Gorrnan et al., Science (1991) 251: 1351-1355). If a cre / loxP recombinase system is used to regulate the expression of the transgene, animals containing transgenes encoding both the cre recombinase and a selected protein are required. Such animals may be provided by the construction of "double" transgenic animals, e.g., by mating two transgenic animals, one of which contains a transgene encoding a selected protein, the other containing a transgene encoding a recombinase. Clones of the non-human transgenic animals described herein may also be produced according to the methods described in Wilmut et al., Nature (1997) 385: 810-813 and in PCT Publications Nos. WO 97/07668 and WO 97/07669 (and which are hereby incorporated by reference in this specification in their entireties). Briefly, a cell, e.g., a somatic cell of the transgenic animal can be isolated and induced to leave the growth cycle and enter the G0 phase. The resting cell can then be fused, e.g., by the use of electrical pulses, to an enucleated oocyte of an animal of the same species from which the resting cell is isolated. The reconstructed oocyte is then cultured in such a way that it develops into a morula or blastocyst., and then transferred to a pseudopregnant female adoptive animal. The offspring born of the female adoptive animal will be a clone of the animal from which the cell has been isolated, e.g., the somatic cell. Additional Uses and Methods of the Invention The nucleic acid molecules, proteins, protein homologs, antibodies of the present invention, and fragments of such moieties, can be used in one or more of the following methods: a) screening assays; b) detection tests (e.g., chromosomal mapping, tissue typing, forensic biology); c) predictive medicine (e.g., diagnostic assays, prognostic assays, clinical observation and pharmacogenomics tests), and d) methods of treatment (e.g., therapeutic and prophylactic). The protein of the invention interacts with other cellular proteins, and thus can be used for (i) regulation of cell proliferation, - (ii) regulation of cell differentiation; (iii) regulation of cell survival, and (iv) regulation of cell function. The isolated nucleic acid molecules of the invention can be used to express the protein of the invention (eg, via a recombinant expression vector in a host cell in gene therapy applications), to detect mRNA of the invention ( eg, in a biological sample) or to detect a genetic lesion in a gene of the invention and modulate the activity of endogenous mRNA, DNA or proteins. Additionally, a protein of the invention can be used to screen drugs or compounds that modulate the activity or expression of the protein, as well as to treat disorders characterized by insufficient or excessive production of endogenous protein. Screening for the production of protein forms having decreased or aberrant activity compared to the wild-type protein can also be performed with the present invention. Additionally, an antibody of the invention can be used to detect and isolate proteins and modulate protein activity. The invention further refers to new agents identified by the screening assays described above and uses thereof for treatments such as those described herein. 1. Detection and Screening Assays Activation of a G protein receptor in the presence of endogenous ligand allows the formation of the G protein receptor complex, thereby leading to GTP binding to protein G. The GTPase domain of the protein G slowly hydrolyses the GTP to GDP resulting in, under normal conditions, the deactivation of the receptor. However, constitutively activated receptors continue to hydrolyze GDP to GTP. A non-hydrolysable protein G substrate, [35 S] GTPγS, can be used to monitor enhanced binding to membranes expressing constitutively activated receptors. Traynor and Nahorski reported that [35 S] GTP? S can be used to monitor the G protein coupling to the membranes in the absence and presence of ligand (Traynor et al., Mol Pharmacol (1995) 47 (4): 848-54). A preferred use of such a test system is for the initial screening of candidate compounds, since the system is applicable generically to all G-protein coupled receptors regardless of the particular G protein that binds to the receptor. Gs stimulates the enzyme adenylyl cyclase, whereas Ga and G0 inhibit said enzyme. As is well known in the art, adenylyl cyclase catalyzes the conversion of ATP to cAMP; therefore, constitutively activated GPCRs that bind to the Gs protein are associated with increased cellular levels of cAMP. Alternatively, constitutively activated GPCRs that could be coupled to the Gx (or Go) protein are associated with decreased cellular levels of cAMP. See "Indirect Mechanism of Synaptic Transmission," Chap. 8, from Neuron to Brain (3rd edition), Nichols et al., Compilers, Sinauer Associates, Inc., 1992. Thus, assays that detect cAMP can be used to determine whether a candidate compound is an inverse agonist for the receptor. A variety of approaches known in the art can be used for the measurement of cAMP. In one embodiment, anti-cAMP antibodies are used in an ELISA-based format. In another embodiment, a second-messenger reporter system assay with whole cells is contemplated (see PCT Publication No. WO 00/22131 and which is incorporated by reference herein in its entireties). A particular embodiment is the SPA assay described later in "Example 5". In a related aspect, cyclic AMP boosts gene expression by promoting the binding of a cAMP-sensitive DNA binding protein or transcription factor (CREB) that is then attached to the promoter at specific sites called cAMP response elements, and boosts gene expression . Thus, reporter systems can be constructed that have a promoter that contains multiple elements of response to cAMP before the reporter gene, e.g., β-galactosidase or luciferase. Additionally, since a receptor bound to activated Gs constitutively causes the accumulation of cAMP, which then activates the gene and the expression of the reporter protein. The reporter protein, such as 3-galactosidase or luciferase, can then be detected using standard biochemical assays (PCT Publication No. WO 00/22131 which is incorporated by reference herein). Other G proteins, such as G0 and Gq, are associated with the activation of the enzyme, phospholipase G, which in turn hydrolyzes the phospholipid, PIP2, releasing two intracellular messengers: diacylglycerol (DAG) and inositol-1,4, 5- triphosphate (IP3). The increased accumulation of PIP3 is associated with the activation of Gq-associated receptors and G0-associated receptors (PCT Publication No. WO 00/22131 which is incorporated by reference herein). Assays that detect the accumulation of IP3 can be used to determine whether a candidate compound is an inverse agonist for a Gq-associated receptor or a G0-associated receptor. The Gq-associated receptors can also be examined using an API reporter assay that measures whether Gq-dependent phospholipase G causes activation of genes containing API elements. Thus, the Gq-associated receptors will show an increase in the expression of said genes, so inverse agonists will demonstrate a decrease in said expression. Also provided in this invention is a method (referred to herein as a "screening assay") for the identification of modulators, i.e. candidate or test compounds or agents (eg, peptides, peptidomimetics, small molecules or others). drugs) that bind to proteins of the invention or have a stimulatory or inhibitory effect on, for example, the expression or activity of the protein. For example, the screening assays described herein could be used to identify compounds that act as antagonists in the receptor that could be useful for the treatment of bronchial asthma. In one embodiment, the invention provides assays for screening candidate compounds or test compounds that bind to or modulate the activity of the membrane-bound form of the protein of the invention, the polypeptide or a biologically active portion thereof. The test compounds of the present invention can be obtained using any of the numerous approaches in the combinatorial library methods known in the art, including: biological libraries; parallel libraries in solid phase or solution phase spatially accessible; methods of synthetic libraries that require decomposition; the "one-pearl un-compound" library method; and methods of synthetic libraries that use selection by affinity chromatography. The approach of biological libraries is limited to peptide libraries, while the other four approaches are applicable to libraries of peptide compounds, non-peptide oligomers or small molecules (Lam, Anticancer Drug Des (1997) 12: 145). Examples of methods for the synthesis of molecular libraries can be found in the art, for example in: Dewitt et al., Proc Nati Acad Sci USA (1993) 90: 6909; Erb et al., Proc Nati Acad Sci USA (1994) 91: 11422; Zuckermann et al., J Med Chem (1994) 37: 2678; Cho et al., Science (1993) 261: 1303; Carrell et al., Angew Chem Int Ed Engl (1994) 33: 2059, - Carell et al., Angew Chem Int Ed Engl (1994) 33: 2061; and Gallop et al. , J Med Chem (1994) 37: 1233. Libraries of compounds can be presented in solution (eg, Houghten Bio / Techni ues (1992) 13: 412-421 or on beads (Lam, Nature (1991) 354: 82-84), chips (Fodor, Nature (1993) 364 : 555-556), bacteria (US Patent No. 5,223,409), spores (US Patents Nos. 5,571,698, 5,403,484, and 5,223,409), plasmids (Culi et al., Proc Nati Acad Sci USA (US Pat. 1992) 89: 1865-1869) or phage (Scott et al., Science (1990) 249: 386-390; Devlin, Science (1990) 249: 404-406; Cwirla et al., Proc Nati Acad Sci USA (1990 ) 87: 6378-6382, and Felici, J Mol Biol (1991) 222: 302-310), all of which descriptions are incorporated herein by reference.

In a particular embodiment of the present invention, an assay is a cell-based assay in which a cell expressing a form of the protein of the invention attached to the membrane, or a biologically active portion thereof, on the cell surface it is contacted with a test compound and the ability of the test compound to bind to the protein is determined. For example, the cell can be a yeast cell or a cell from a mammal. The determination of the ability of the test compound to bind to the protein can be carried out, for example, by coupling the test compound with a radioisotope or enzyme tracer such that the binding of the test compound to the protein of the invention or Biologically activated thereof can be determined by detection of the labeled compound in a complex. For example, the test compounds can be labeled directly or indirectly with 125 I, 35 S, 14 C or 3 H, and the radioisotope can be detected by direct counting of radio emission or by scintillation counting. Alternatively, the test compounds can be labeled enzymatically, for example with horseradish peroxidase, alkaline phosphatase or luciferase, and the enzymatic tracer can be detected by determining the conversion of an appropriate substrate into a product. In a particular embodiment, the assay comprises contacting a cell expressing a form of the protein of the invention fixed to the membrane or a biologically active portion thereof, on the cell surface with a known compound that binds to the protein to form a test mixture; and then contacting the test mixture with a test compound and determining the ability of the test compound to interact with the protein, where the determination of the ability of the test compound to interact with the protein comprises determining the capacity of the compound of test to be preferably fixed to the protein of the invention or a biologically active portion thereof in comparison with the known compound. In another embodiment, an assay is a cell-based assay that comprises contacting a cell that expresses a form of the protein of the invention attached to the membrane or a biologically active portion thereof, on the cell surface with a Test compound and determine the ability of the test compound to modulate (eg, stimulate or inhibit) the activity of the protein or biologically active portion thereof. The determination of the ability of the test compound to modulate the activity of the protein of the invention or a biologically active portion thereof can be accomplished, for example, by determining the ability of the protein to bind to or interact with a target molecule. As used herein, a "target molecule" is a molecule with which the protein of the invention binds or interacts in nature, for example, a molecule on the surface of a cell that expresses the protein of the invention , a molecule existing on the surface of a second cell, a molecule existing in the extracellular medium, a molecule associated with the inner surface of a cell membrane, or a cytoplasmic molecule. A target molecule may be another molecule or a protein or polypeptide of the present invention. In one embodiment, a target molecule is a component of a signal transduction pathway that facilitates the transduction of an extracellular signal (eg, a signal generated by the binding of a compound to a protein of the invention attached to the membrane) through from the cell membrane and into the interior of the cell. The target may be, for example, a second intercellular protein having catalytic activity or a protein that facilitates the association of downstream signaling molecules. The determination of the ability of the protein of the present application to interact with a dihan molecule can be carried out by any of the methods described above to determine direct fixation. In a particular embodiment, the determination of the ability of the protein of the invention to bind to or interact with a target molecule can be performed by determining the activity of the target molecule. For example, the activity of the target molecule can be determined by detection of the induction of a second cellular target messenger (eg, intracellular Ca2 +, diacylglycerol, IP3, etc.), detection of the catalytic / enzymatic activity of the target on an appropriate substrate, detection of the induction of a reporter gene (eg, a sensitive regulatory element operably linked to a nucleic acid encoding a detectable marker, eg luciferase) or detection of a cellular response, eg, differentiation, proliferation or cellular function. A particular embodiment is described later in "Example 4", wherein the receptor of the invention is coupled to Gal6 to elicit a calcium response. The present invention further extends to a cell-free assay comprising contacting a protein of the invention, or a biologically active portion thereof, with a test compound, and determining the ability of the test compound to bind to the protein or biologically active portion thereof. The binding of the test compound to the protein can be determined directly or indirectly as described above. In a preferred embodiment, the assay includes contacting the protein of the invention or biologically active portion thereof with a known compound that binds the protein to form a test mixture.; and then contacting the test mixture with a test compound and determining the ability of the test compound to interact with the protein. In this case, the determination of the ability of the test compound to interact with the protein of the invention comprises determining the ability of the test compound to preferentially bind to the protein or biologically active portion thereof in comparison with the known compound. Another cell-free assay of the present invention involves contacting the protein of the invention or biologically active portion thereof with a test compound and determining the ability of the test compound to modulate (eg, stimulate or inhibit) the activity of the protein or biologically active portion thereof. The determination of the ability of the test compound to modulate the activity of the protein can be carried out, for example, by determining the ability of the protein to bind to a target molecule by one of the methods described above to determine direct fixation. In an alternative embodiment, the determination of the ability of the test compound to modulate the activity of the protein can be performed by determining the ability of the protein to further modulate a target molecule. For example, the catalytic / enzymatic activity of the target molecule on an appropriate substrate can be determined as previously described. Another additional assay without cells of the present invention comprises contacting the protein of the invention or biologically active portion thereof, with a known compound that binds the protein to form an assay mixture, contacting the assay mixture with a test compound and determining the ability of the test compound to interact with the protein. The step for determining the ability of the test compound to interact with the protein comprises determining the ability of the protein to preferentially bind to or modulate the activity of a target molecule. The receptors can be activated by molecules other than ligands that do not necessarily inhibit the binding of a ligand but cause structural changes in the receptor that allow G protein binding or, perhaps aggregation, dimerization or clustering of the receptor that can cause activation. For example, antibodies can be generated for the various portions of the receptor of the invention that are facing the cell surface. Such antibodies activate a cell via the G protein cascade as determined by standard assays, such as the monitoring of cAMP levels or intracellular Ca + 2 levels. Since molecular mapping, and particularly epitope mapping, is involved, monoclonal antibodies may be preferable. Monoclonal antibodies can be generated both for an intact receptor expressed on the cell surface and for known peptides that are formed on the cell surface. The method of Geysen et al., U.S. Pat. No. 5,998,577, can be practiced to obtain a plurality of relevant peptides. The antibodies found to activate the receptor of the invention can be modified to minimize activities foreign to receptor activation, such as complement fixation. Thus, antibody molecules can be truncated or mutated to minimize or eliminate activities other than receptor activation. For example, for certain antibodies, only the antigen binding portion is necessary. Thus, the Fc portion of the antibody can be eliminated. Cells that express the receptor of the invention can be exposed to antibodies to activate the receptor. Activated cells are then exposed to various molecules in order to identify those molecules that modulate receptor activity, and result in higher levels of activation or lower levels of activation. Molecules that reach such targets can then be assayed on cells that express the receptor of the invention without antibody to observe the effect on non-activated cells. The target molecules can then be assayed and modified as candidate drugs for the treatment of disorders associated with altered metabolism using known techniques. The cell-free assays of the present invention are suitable for use both in the soluble form and in the membrane-bound form of the protein of the invention. In the case of assays without cells comprising the membrane-bound form, it may be desirable to use a solubilizing agent such that the form fixed to the membrane is maintained in solution. Examples of such solubilizing agents include nonionic detergents such as n-octylglucosido, n-dodecylglucosido, n-dodecylmalto-been, octanoyl-N-methylglucamide, decanoyl-N-methylglucamide, TRITON X-100, TRITON X-14, THESIT, isotridecilpoli (ethylene glycol ether) n, 3- [(3-colamidopropyl) dimethylamino] -1-propane-sulfonate (CHAPS), 3- [(3-colamidopropyl) dimethylamino] -2-hydroxy-l-propane-sulfonate (CHAPSO) or N-dodecyl-N, N-dimethyl-3-ammonium-l-propane-sulfonate. In more than one embodiment of the above assay methods of the present invention, it may be desirable to immobilize the protein of the invention or a target molecule thereof to facilitate the separation of the complexed and non-complexed forms of one of the proteins or both, as well as facilitate the automation of the trial. The binding of a test compound to the protein of the invention or the interaction of the protein with a target molecule in the presence and absence of a candidate compound can be carried out in any container capable of containing the reactants. Examples of such packages include microtiter plates, test tubes and i-cro-centrifuge tubes. In one embodiment, a fusion protein can be provided that adds a domain that allows one or both of the proteins to bind to a matrix. For example, glutathione-S-transferase / protein fusion proteins of the invention or glutathione-S-transferase / target fusion proteins can be adsorbed onto glutathione-SEPHAROSE beads (Sigma Chemical, St. Louis, MO). Alternatively, microtiter plates derivatized with glutathione are then combined with the test compound. Subsequently, either the non-adsorbed target protein or the protein of the invention and the mixture are incubated under conditions conducive to the formation of a complex (e.g., under physiological conditions for salt and pH). After incubation, the beads or wells of the microtiter plate are washed to remove any unfixed components, and the presence of complex formation is measured directly or indirectly. Alternatively, the complexes can be dissociated from the matrix and the level of fixation or activity determined using standard methods. Other methods for immobilizing proteins on matrices can also be used in the screening assays of the invention. For example, either the protein of the invention or a target molecule thereof can be immobilized using the conjugation of biotin and streptavidin. The protein of the invention or dyne molecules. The protein of the invention or biotinylated target molecules (s) can be prepared from biotin-NHS (N-hydroxy-succinimide) using methods well known in the art (eg, biotinylation kit, Pierce Chemcals, Rockford, IL) and immobilized in wells of 96-well plates coated with streptavidin (Pierce Chemicals). Alternatively, antibodies that are reactive with the proteins of the invention or a target molecule, but do not interfere with the binding of the protein of the invention to the target molecule, can be derivatized in the wells of the plate. After incubation, the unbound target or protein of the invention can be trapped in the wells by conjugation of antibodies. Methods for the detection of such compounds, in addition to those described above for the GST-immobilized complexes, include complex immunodetection using antibodies reactive with the proteins of the invention or the target molecule, as well as enzyme-linked assays that are based on detection of an enzymatic activity associated with the protein of the invention or the target molecule. In another embodiment, modulators of protein expression are identified in a method in which a cell is contacted with a candidate compound, and the expression of mRNA or protein of the invention in the cell is determined. The level of expression of mRNA or protein in the presence of the candidate compound is compared to the level of expression of mRNA or protein in the absence of the candidate compound. The candidate compound can then be identified as an expression modulator based on said comparison. For example, when mRNA or protein expression is greater (greater to a statistically significant degree) in the presence of the candidate compound than in the absence thereof, the candidate compound is identified as a stimulator or agonist of mRNA or protein expression. . Alternatively, when mRNA or protein expression is lower (less to a statistically significant degree) in the presence of the candidate compound than in the absence thereof, the candidate compound is identified as an inhibitor or antagonist of mRNA or protein expression. If the activity is reduced in the presence of ligand or agonist, or in a constitutively expressing cell it is lower than the baseline, the candidate compound is identified as an inverse agonist. The level of mRNA or protein expression in the cells can be determined by methods described herein for the detection of mRNA or protein. In still another aspect of the invention, the proteins of the invention can be used as "bait proteins" in a double hybrid assay or triple hybrid assay (see, e.g., U.S. Patent No. 5,283,317).; Zervos et al., Cell (1993) 72: 223-232; Madura et al., J Biol Chem (1993) 268: 12046-12054; Bartel et al., Bio / Techniques (1993) 14: 920-924; Iwabuchi et al., Oncogene (1993) 8: 1693-1696; and PCT publication No. WO 94/10300, all of which descriptions are incorporated herein by reference), to identify other proteins that bind to or interact with the protein of the invention and modulate the activity of the protein of the invention. Such binding proteins are also probably involved in signal propagation by the proteins of the invention such as elements located upstream or downstream of the signaling path. Since the present invention makes possible the production of large quantities of pure protein of the present application, the physical characterization of the conformation of areas of similar function for rational drug design can be ascertained. For example, intracellular and extracellular domains are regions of particular interest. Once the shape and ionic configuration of a region has been discerned, candidate drugs can be configured which should interact with said regions and then be tested on intact cells, animals and patients. Methods that could allow the derivation of such information from the 3-D structure include X-ray crystallography, NMR spectroscopy, molecular modeling, and so on. The 3-D structure can also lead to the identification of analogous conformation sites in other known proteins in which there are known drugs that interact at this site. These drugs, or derivatives thereof, may find use with the protein of the present invention. The screening assays described above could be particularly interesting in the identification of compounds that act as agonist, partial agonist, antagonist, inverse agonist or modulator of the receptor of the invention providing a means to identify compounds for the treatment of diseases that include, but without limitation, bronchial asthma, COPD, allergic rhinitis, allergic dermatitis, allergic conjunctivitis, systemic mastocytosis and ischemic reperfusion injury. The invention further refers to new agents identified by the screening assays described above and uses thereof for treatments such as those described herein. Portions or fragments of the DNA sequences of the present invention can be used in numerous ways as polynucleotide reagents. For example, the sequences can be used to: (i) map the respective genes on a chromosome and, thereby, localize gene regions associated with a genetic disease; (ii) identify an individual from a tiny biological sample (tissue typing); and (iii) assist in the forensic identification of a biological sample. The applications are described in the following subsections. 2. Chromosomal Mapping Once the sequence (or a portion of the sequence) of a gene has been isolated, the sequence can be used to map the location of the gene of the present invention to a chromosome. Accordingly, nucleic acid molecules described herein or fragments thereof can be used to map the location in a genome. The mapping of the location of the sequence in a genome, particularly a human genome, is an important first step in the correlation of the sequences with genes associated with a disease. Briefly, genes in a genome can be mapped by preparation of PCR primers (preferably 15-25 bp in length) from the sequences described in SEQ ID NO: 1. The primers are used for PCR screening of somatic cell hybrids containing individual human chromosomes. Only those hybrids containing the human gene corresponding to the sequences of the invention produce an amplified fragment. Hybrids of somatic cells are prepared by fusion of somatic cells from different mammals (e.g., human and mouse cells). As the hybrids of human and mouse cells grow and divide, human chromosomes are usually lost in random order, but mouse chromosomes are retained. Using media in which mouse cells can not grow (due to the leakage of a particular enzyme), but in which human cells can grow, the only human chromosome containing the gene encoding the necessary enzyme is retained. drá Using various means, hybrid cell line panels are established. Each cell line in a panel contains either a single human chromosome or a small number of human chromosomes and a whole series of mouse chromo- somes, which allows easy mapping of individual genes to specific human chromosomes. (D'Eustachio et al., Science (1983) 220: 929-924) Somatic cell hybrids containing only fragments of human chromosomes can also be produced using human chromosomes with translocations and deletions.The PCR mapping of somatic cell hybrids is A quick procedure for assigning a particular sequence to a particular chromosome Three or more sequences per day can be assigned using a single thermocycler Other mapping strategies that can be used similarly to map a sequence to a particular chromosome in a genome include hybridization in itself (described in Fan et al., Proc Nati Acad Sci USA (1990) 87: 6223-27), pre-screening with labeled chromosomes classified by flow separation and pre-screening by hybridization to chromosome-specific cDNA libraries. Fluorescence in situ hybridization (FISH) of a DNA sequence to a metaphase chromosome extension can also be used to provide a precise chromosome location in a single step. Chromosome extensions can be made using cells in which the division has been blocked in metaphase by a chemical, e.g., colcemid, which breaks the mitotic spindle. Chromosomes can be treated briefly with trypsin and then stained with Giemsa. A pattern of light and dark bands develops on each chromosome so that the chromosomes can be identified individually. The FISH method can be used with a DNA sequence as short as 500 or 600 bases. However, clones of length greater than 1000 bases may have a higher probability of being fixed to a single chromosomal location with sufficient signal strength for simple detection. Preferably 1000 bases and, more preferably, 2000 bases will be sufficient to obtain satisfactory results in a reasonable amount of time. For a review of the technique, see Verma et al. (Human Chromosomes: A Manual of Basic Techniques (Pergamon Press, New York, (1988)) • Chromosome mapping can be inferred "in silico", and using statistical considerations, such as lod or simple proximity registers Reagents for chromosome mapping they can be used individually to locate an individual site on a chromosome Additionally, reagent panels can be used to mark multiple sites and / or multiple chromosomes Reagents corresponding to flanking regions of the gene are actually preferred for mapping purposes The coding sequences are more likely to be conserved within gene families, thus increasing the possibility of cross-hybridization during chromosomal mapping Once a sequence has been mapped to a precise chromosomal location, the physical position of the sequence on the chromosome can be correlated with data of genetic maps. (Data of this type are found, for example, in McKusick, Mendelian Inheritance in Man available online through Johns Hopkins University, Welch Medical Library). The relationship between genes and disease, mapped to the same chromosomal region, can then be identified by linkage analysis (common inheritance of physically adjacent genes), described, e.g., in Egeland et al., Nature (1987) 325: 783-787.

In addition, differences in DNA sequences between affected and unaffected individuals can be determined with a disease associated with the protein of the invention. If a mutation is observed in some or all of the affected individuals, but not in any unaffected individuals, then it is likely that the mutation is the causative agent of the particular disease. The comparison of affected and unaffected individuals generally involves looking first for structural alterations in the chromosomes such as deletions or translocations that are visible from chromosomal extensions or detectable using PCR based on said DNA sequence. Finally, complete sequencing of genes from several individuals can be performed to confirm the presence of a mutation and distinguish mutations of polymorphisms. 3. Diagnostic Assays An illustrative method for detecting the presence or absence of a nucleic acid or protein of the invention in a biological sample involves obtaining a biological sample from an individual subject of the assay and contacting the biological sample with a compound or an agent capable of detecting the protein or nucleic acid (eg, mRNA or genomic DNA) such that the presence is detected in the biological sample. A preferred agent for the detection of mRNA or genomic DNA is a labeled nucleic acid probe capable of hybridizing to the mRNA or genomic DNA of the invention. The nucleic acid probe can be, for example, a full-length nucleic acid, such as the nucleic acid of SEQ ID NO: a portion thereof, such as an oligonucleotide of at least 15, 30, 50, 100, 250 or 500 or more nucleotides in length and sufficient to hybridize specifically under severe conditions to mRNA or genomic DNA. Other probes suitable for use in the diagnostic assays of the invention are described herein.

A particular agent for detection of the protein of the invention is an antibody capable of binding to the protein, preferably an antibody with a detectable tracer. The antibodies can be polyclonal, chimeric or, more preferably, monoclonal. An intact antibody or fragment thereof (eg, Fab or F (ab ') 2) can be used. The term "biological sample" is intended to include tissues, cells and biological fluids isolated from an individual, as well as tissues, cells and fluids present in an individual. That is, the detection method of the invention can be used to detect mRNA, protein or genomic DNA in a biological sample both in vi tro and in vivo. For example, in vi tro methods for mRNA detection include Northern hybridization and in situ hybridization. In vi tro methods for detection of the protein include ELISA, Western blot, immunoprecipitation and immuno-fluorescence. In vitro techniques for genomic DNA detection include Southern hybridization. Additionally, in vivo methods for protein detection include the introduction into an individual of an antibody labeled against the protein of the invention. For example, the antibody can be labeled with a radioactive label, whose presence and location in an individual can be detected by standard methods of imaging. In one embodiment, the biological sample contains protein molecules of the subject subject of the assay. Alternatively, the biological sample may contain mRNA molecules of the subject subject of the assay or genomic DNA molecules of the subject subject of the assay. A particular biological sample having applications in this memory is a sample of neutrophils isolated from an individual by conventional means. Therefore, the association with a disease and identification of the nucleic acid polymorphism or the diagnostic protein for the carrier or the affected one may be beneficial in the development of prognostic or diagnostic tests. For example, it would be beneficial to have a prognostic or diagnostic test for rheumatoid arthritis, asthma, Crohn's disease, etcetera. The expression of the nucleic acid or the protein of the invention is elevated in cells associated with activated or inflammatory conditions. Disorders associated with inflammation include anaphylactic conditions, colitis, Crohn's disease, edematous states, contact hypersensitivity, allergy, other forms of arthritis, meningitis and other conditions in which the immune system reacts to an attack by vascular dilation, heat, accumulation of cells, fluids, etc. in one place, resulting in swelling and analogous symptoms. Thus, a disorder in the metabolism can be a diagnosis of rheumatoid arthritis. In addition, the molecular mechanism of rheumatoid arthritis may be detectable; for example, there may be a diagnostic SNP, RFLP, variability of expression level, variability of function, etc., which may be detectable in a tissue sample, such as a blood sample. In another embodiment, the methods additionally involve obtaining a biological sample from an individual control, contacting the control sample with a compound or agent capable of detecting protein, mRNA or genomic DNA of the invention, in such a way that the presence and quantity of protein, mRNA or genomic DNA is detected in the biological sample, and the final comparison of the presence and amount of protein, mRNA or genomic DNA in the control sample with the presence and amount of protein, mRNA or DNA genomic in a test sample. 4. High Capacity Assays of Chemical Libraries Any of the assays for compounds capable of modulating the activity of the nucleic acid or protein of the invention are suitable for high capacity screening. High capacity counting systems are commercially available (see, eg, Zymark Corp., Hopkinton, MA; Air Technical Industries, Mentor, OH; Beckman Instruments, Inc. Fullerton, CA; Precision System, Inc., Natick, MA, etc.). .). These systems typically automate entire procedures including all sample and reagent pipetting, liquid dispensing, timed incubations, and final microplate readings on the detector (s) appropriate for the assay. These configurable systems provide high capacity and fast start-up, as well as a high degree of flexibility and purposeful adaptation. The manufacturers of such systems provide detailed protocols of the various high-capacity protocols. Thus, for example, Zymark Corp. provides technical bulletins that describe screening systems for the detection of gene transcription modulation, ligand application, and so on. 5. Cases The invention also encompasses kits for detecting the presence of the nucleic acid or protein of the invention in a biological sample (a test sample). Such kits can be used to determine whether an individual suffers from or is at increased risk of developing a disorder associated with aberrant expression (e.g., an immunological disorder). For example, the kit may comprise a compound or labeled agent capable of detecting the protein or mRNA of the invention in a biological sample and means for determining the amount of nucleic acid or protein in the sample (eg, an antibody or an oligonucleotide probe). ). Cassettes may also be used to provide results that indicate whether the subject subject is at or is at risk of developing a disorder associated with aberrant expression of the nucleic acid or protein of the invention, if the amount of protein or mRNA is higher or lower than a normal level. In the case of antibody-based kits, the kit may comprise, for example: (1) a first antibody (e.g., attached to a solid support) that binds to the protein of the invention; and, optionally, (2) a second, different antibody, which binds to the protein of the invention or to the first antibody and is conjugated to a detectable agent. If the second antibody is not present, then the first antibody can be detectably labeled, or alternatively, another molecule that binds to the first antibody can be detectably labeled. In any case, a labeled fixing moiety is included to serve as the reportable detectable molecule, as is known in the art. In the case of oligonucleotide-based kits, a kit of the present invention can comprise, for example: (1) an oligonucleotide, eg, a detectably-labeled oligonucleotide, which hybridizes to a nucleic acid sequence of the invention or (2) a pair of primers useful for amplification of a nucleic acid molecule of the invention. The case may also comprise, e.g., a buffering agent, a preservative or a protein stabilizing agent. The kit can also comprise the components necessary to detect the detectable agent (e.g., an enzyme or a substrate). Additionally, the case may also contain a control sample or series of control samples that can be tested and compared to the test sample. Each component of the case is usually included within a single package, and all of the various packages are contained within a single package. Instructions and basic information may also be included. 6. Monitoring of Effects During Clinical Trials Monitoring of the influence of agents (eg, drugs or compounds) on the expression or activity of the nucleic acids or proteins of the invention (eg, the ability to modulate proliferation, differentiation and / or aberrant cell function) can be applied not only in the basic scrutiny of drugs, but also in clinical tests. For example, the efficacy of an agent, as determined by a screening assay such as those described herein, to increase gene expression, protein levels or protein activity, can be monitored in clinical trials of individuals. which exhibit decreased gene expression, protein levels or protein activity. Alternatively, the efficacy of an agent, as determined by a screening assay, to decrease gene expression, protein levels or protein activity, can be monitored in clinical trials of individuals exhibiting gene expression, protein levels or increased protein activity. In such clinical tests, the expression or activity and preferably, those of other genes that have been implicated, for example, in a cell proliferation disorder, can be used as a marker of the immunological sensitivity of a particular cell. For example, and without limitation, genes, including the genes of the invention, which are modulated in the cells by treatment with an agent (eg, a compound, a drug or a small molecule) that modulates the activity can be identified. of the nucleic acid or the protein of the invention (eg, such as is identified in a screening assay described herein). Thus, to study the effect of the agents on cell proliferation disorders, for example, in a clinical trial, cells can be isolated and RNA prepared and analyzed for the expression levels of the nucleic acids of the invention and other genes involved in the disorder. The levels of gene expression (ie, a pattern of gene expression) can be quantified by Northern blot analysis or RT-PCR, as described herein, or alternatively by measuring the amount of protein produced by one of the methods described herein or by measurement of the activity levels of genes of the invention or other genes. In this way, the pattern of gene expression can serve as a marker, indicative of the physiological response of the cells to the agent. Accordingly, the response state can be determined before and at various times during the treatment of the individual with the agent. In a particular embodiment, the present invention provides a method for monitoring the effectiveness of treatment of an individual with an agent (eg, an agonist, antagonist, peptidomimetic, protein, peptide, nucleic acid, stick molecule or other candidate drug identified by the assays). of scrutiny described herein) comprising the steps of (i) obtaining a pre-administration sample from an individual prior to administration of the agent; (ii) detecting the level of expression of a protein, mRNA or genomic DNA of the invention in the pre-administration sample, - (iii) obtaining one or more samples postadministration of the individual; (iv) detecting the level of expression or activity of the genomic protein, mRNA or DNA of the invention in the post-administration samples; (v) comparing the level of expression or activity of the genomic protein, mRNA or DNA of the invention in the sample pre-administered with the genomic protein, mRNA or DNA of the invention in the sample or post-administration samples; and (vi) alter the administration of the agent to the individual in agreement, thereby. For example, an increased administration of the agent to increase the expression or activity of the genomic protein, mRNA or DNA of the invention may be desirable at levels greater than those detected, i.e. to increase the effectiveness of the agent. Alternatively, decreased administration of the agent may be desirable to reduce the expression or activity of the genomic protein, mRNA or DNA of the invention to levels lower than those detected, i.e. to decrease the effectiveness of the agent. The following examples describe the invention in more detail. EXAMPLES Example 1 Cloning of an Initial Exodus DNA Fragment from the Cobayus DP Receptor The cloning of the Cavia porcellus DP receptor cDNA was initiated by cloning an exonic fragment of the DP receptor of genomic DNA using PCR. A range of PCR primers were designed using the conserved regions of the sequences of the human (U31332), mouse (NM_008962) and rat (NM_022241) receptors that were aligned using the Sequencher program (Gene Codes, Ann Harbor MI) . The genomic DNA of Cavia porcellus (guinea pig) was purchased from CeMines (Evergreen, Co.). The initiator used to amplify a 420 bp fragment of Cavia genomic DNA was made with primers 675_Topo_F3 (SEQ ID NO: 3: GGGACACCCTTTCTTCTACAA) and 675_Topo_R2 (SEQ ID NO: 4: GAACACATGGTGAAGAGCACTG). The PCR product was cloned using TOPO-TA cloning (Invitrogen, Carlsbad CA) and the insert was sequenced on an ABI 3100 DNA sequencer according to the manufacturer's instructions. 3 'and 5' RACE-PCR cloning The resulting DNA sequence was aligned to the human, mouse and rat DP sequences. The alignment revealed that the sequence of the PCR product was homologous, but different, from the consensus of DP receptors of the species examined (Figure 3). The Cavia porcellus DP receptor consensus was used to design additional primers in order to extend the cloned sequence using the Rapid Amplification of DNA Ends (RACE) method. In order to obtain the 3 'end of the DP receptor transcript, the SMART RACE system from Clontech (a subsidiary of BD Biosciences, Palo Alto, CA) was used. The primer 675_GP_3 'RACE_F (SEQ ID NO: 5: GTGCTCGTGGCGCG-GTGTG) was used with Cavia lung mRNA converted to a cDNA template to extend the Cavia DP receptor mRNA sequence. The RACE products were cloned in PCR4-Topo (Invitrogen, Carlsbad CA), sequenced and aligned as described above to reveal the full 3 'extension of the DP receptor coding sequence. In order to isolate the 5 'end of the Cavia DP receptor cDNA, SMART RACE was performed with the primer 675_Rev_P2 (SEQ ID NO: 6: CACATGGTGAAGAGCACGGTCATGA) and a 1 kb PCR product was generated. The purified PCR product was used as a template for RACE 5 'nested using the primer 675_RACE_R9 (SEQ ID NO: 7: TCACCAGGCACTTGCCTAGCAGGTCTGT). The RACE products were cloned in PCR4-Topo (Invitrogen), and sequenced and aligned as described above to reveal the full 5 'extension of the DP receptor coding sequence. CDNA Construction Coding of the Cobayo DP Receptor The coding sequence of the DP receptor was identified using the Gene Construction Kit program (Textco, Keene NH). "Gateway" primers compatible with cloning were designed to flank the coding sequence (GW675, direct initiator SEQ ID NO: 8: AAAAGCAGGCTTAGGAATGTCCTTCTATCCCTGCAACAC; GW675, reverse primer SEQ ID NO: 9: AAGAAAGCTGGGTCTCACAGACTGGATTCCACGTTAG), and were used in a PCR reaction with cDNA generated from the Cavia porcellus lung cells stimulated with ovalbumin. PCR was performed using 10 units of thermo-stable PFU Turbo polymerase (Stratagene, La Jolla CA), and 100 ng of template cDNA. A 1.1 kb DNA fragment was generated, purified by gel electrophoresis chromatography by the QiaQuick protocol (Qiagen) and cloned into the pDONR201 vector using the Gateway BP recombinase cloning method (Invitrogen). The cloning reactions were transformed into DH5-alpha from E. coli and mini-prep DNA from the resulting colonies was subjected to DNA sequencing to confirm the cloning of the complete coding sequence of the DP receptor. Example 2 Analysis by Northerm transfer Northerm transfer analysis was performed with the initial genomic DNA fragment of the Ca-via DP receptor (Figure 5). Lung was isolated from male Hartley guinea pigs that had faced ovalbumin or had not received ovalbumin treatment. The expression of total lung RNA of Cavia porcellus not confronted (lane 2) was compared with the expression of total lung RNA of Cavia porcellus facing ovalbumin (lane 3). The loaded RNA was equivalent, as determined by spectroscopy and intensity of the 18S band of RNA. The Northerm transfer for the DP receptor identified a 3-4 kb mRNA in the guinea pig lung, a size consistent with the transcript consigned for mouse and human DP (Hirata et al., 1994; Boie et al., 1995). ). This mRNA was significantly upregulated in the lungs of guinea pigs that had been sensitized and confronted with ovalbumin, a result comparable to that previously reported for the DP receptor that was upregulated in the mouse lung after confronting an antigen ( Matsuoka et al., 2000). These data support the importance of PD in the asthmatic response in the lung of the guinea pig. Example 3 Sequence Analysis of the Guinea Pig Receptors to Orthologs The nucleotide sequence (Figure 1) and the deduced amino acid sequence (Figure 2) for the guinea pig DP receptor are shown. The guinea pig DP cDNA contains an open reading frame of 1032 bp that encodes a protein of 345 amino acids with calculated molecular weight of 38,250. The guinea pig DP protein contains two potential N-glycosylation sites, Asn-7 at the amino terminus and Asn-86 at the first extracellular loop. There are also 2 potential phosphorylation sites by protein kinase C, Ser-46 and Thr-140 located in the first and third cytoplasmic loops, respectively. Figure 1 shows the nucleotide sequence of the guinea pig DP receptor compared to the corresponding sequences of human, rat and mouse DP. Analogously at the protein level, the sequence identity against the DP receptor of the guinea pig was 66% for human DP, 63% for mouse DP and 65% for rat DP (Figure 2). Hydropathy analysis confirmed the presence of seven putative transmembrane domains that mapped identical conserved areas that had been previously defined in mouse, rat, and human DP sequences. The conservation of the sequence was the maximum in the transmembrane domains between the DP orthologs. Two sections of sequence that, as previously reported, were characteristically conserved among the GPCRs of the prostanoid family (Hirata et al., 1994) were also present in the guinea pig DP protein: QYCPGTWCR in the second extracellular loop and RFLSVISIVDPWIFI in the seventh transmembrane domain were identical among all DP orthologs. The extracellular loop between the TMDs VI and VII also showed differences between the species. This loop varied between orthologs and had lengths of 24, 21, 21 and 18 amino acids in the human DP, rat, mouse and guinea pig, respectively. Particularly interesting is the loss of 6 amino acids in the guinea pig DP between the VI and VII TMDs compared to the human DP receptor. Additionally, 3 amino acids in this region were also removed in both mouse and rat DP receptors. Kobayashi et al. (2000) generated a series of IP-DP chimeric receptors to define the regions that confer the binding selectivity of DP ligands. It is interesting to note that one of the regions that these authors deduced was important in the selective and potent fixation of PGD2 was the transmembrane region VI-VII, exactly the same region shown to be 6 amino acids shorter in this newly cloned guinea pig DP receptor. The differences of orthologs in ligand affinity or compound potency may be due to interactions within the TMD loop VI-VII and to alterations in this loop in the guinea pig receptor. The first and third intracellular loops are 3 and 5 short amino acids in the guinea pig DP protein, whereas in mouse, human and rat DP proteins these intracellular loops are all of identical size. Kobayashi et al. Also highlighted the importance of the transmembrane domain 1 in the region of the first extracellular loop for PGD2 binding. Since the first intracellular steer is 3 short amino acids in the guinea pig DP compared to the human, mouse or rat DP, this region should be an additional region contributing to the affinity of receptor binding. Additionally, this region of the receptor could be attributed to the differences observed between the affinities of the compounds for human and guinea pig DP. The third intracellular loop (between the TMDs V and VI) is 5 amino acids shorter in guinea pig DP, providing another region of the receptor contributing to the functional relevance of PGD2. Example 4 Construction of the Mammalian Expression Vectors pEAKlO-gpDP and pEAKIO-mDP A full-length cDNA for the mouse DP receptor was obtained by PCR and cloned into the pDONR201 vector using the Gateway recombinase cloning method BP. This generated a mouse DP vector that was analogous to the guinea pig DP vector described above. DNA sequencing confirmed that this mouse DP cDNA was identical to the mouse DP sequence described previously, defined by Genbank accession number NM_008962. For expression studies, the mouse and guinea pig DP receptors were subcloned by an LR reaction in a pEAKIO expression vector (Edge Biosystems) that had been previously adapted by Gateway. The Gateway adaptation of the pEAKIO vector was performed by digestion with EcoRI and subsequent Klenow filling for cloning of the Gateway cassette in the vector. The resulting pEAKIO-gpDP and pEAKIO-mDP vectors were used for generation of stable cell lines as described below. Generation of a line of HEK293-Ga16 cells The cDNA encoding human Gal6 was cloned as described (Amatruda et al., 1991). Briefly, total RNA from human promyelocytic leukemia cells H-60 was isolated and used as a template for the PCR-mediated synthesis of cDNA encoding Gal6. The resulting PCR product was cloned into the pHOOK-3 expression vector (Invitrogen), which also coexpresses a single chain antibody (sFv) to allow convenient enrichment of transfected cells using a panning protocol with magnetic beads coated with hapten (Chesnut et al. al., 1996). HEK293 cells were transfected with the constructed plasmid (pGald), selected with Zeocin and the positive clones were enriched using magnetic pellets in accordance with the protocols supplied by the vendor. For final purification and selection, single clones were individually cultured and tested for functional expression of G6 by additional transfection of an aliquot with an expression vector for an arbitrarily selected GPCR that naturally coupled to Gas (GIP receptor)., with subsequent assay of the transfected cells for calcium signaling using the FLIPR device from Molecular Devices Corp. Expression of pEAKIO-gpDP and pEAKIO-mDP in HEK293-Gal6 cells The vectors pEAKIO-gpDP and pEAKIO-mDP were transfected to the HEK293-Go cell line; 16 using Lipofectamine 2000 (Gibco) as described by the manufacturer. The transfected cells were cultured under selection with 1 μg / ml puromycin and 250 μg / ml zeocin for 5 weeks. DP receptor expression was monitored in the population of transfected cells by measuring the intracellular calcium release in response to stimulation with PGD2. Intracellular Calcium Assays For functional characterization, the newly cloned guinea pig DP receptor was stably transfected to HEK293-Gal6 cells and for comparison an equivalent cell line was generated with the mouse DP receptor. Both the cell lines expressing the DP receptor and the parental cell line that did not express any transfected DP receptor were evaluated in a second messenger assay using the Gal6 receptor binding to elicit a calcium response. Intracellular calcium measurements were performed using non-transfected HEK293-Gal6 cells or cells transfected with the expression vectors pEAKIO-gpDP or pEAKIO-mDP. The transfected and non-transfected cells were distributed in 384-well plates at a rate of 10,000 cells per well. The cells were washed 3 times with calcium assay buffer. The cells were then incubated with 4 μM of the calcium loading dye Fura-4 / AM (Molecular Probes) at 37 ° C for x min. The unincorporated Fura-4 / AM was removed by 3 additional washes with calcium assay buffer. Intracellular calcium was measured after stimulation with PGD2 or tam-pon of cells loaded with Fura-4 / AM using a FLIPR instrument (Molecular Devices Corp.). As shown in Figure 6, stimulation with PGD2 caused strong increases in intracellular calcium mobilization both in cell lines expressing guinea pig DP and in those expressing mouse DP, with EC50 values of 1.4 nM and 18 nM, respectively. The maximum release of calcium in both cell lines was comparable. In contrast, the parental HEK293-Go; 16 cell line exhibited only a calcium response for very high PGD2 concentrations (ie, greater than 10 μM PGD2). Example 5 SPA assay of c MP An additional functional characterization of the newly cloned guinea pig DP receptor used the natural signaling pathway for DP, the stimulation of cAMP production by adenylate cyclase. The transfected or non-transfected cells were plated at 40,000 cells per well of a 96-well plate. After incubation overnight at 37 ° C, the medium was replaced and the cells were stimulated with defined concentrations of PGD2 for 15 minutes. The accumulation of cAMP was measured in the cells stimulated using the Direct SCAN Screening Assay System of cAMP (Amersham) according to procedures specified by the manufacturer. As shown in Figure 7, the guinea pig DP cell line exhibited a satisfactory cAMP response to stimulation with PGD2, which was comparable to the response of the mouse DP receptor. The EC50 values were 0.8 nM and 0.5 nM for the guinea pig and mouse DP cell line, respectively, and the maximum response was comparable with both receptors. In contrast, the parental HEK293-Gal6 cell line exhibited no increase in intracellular cAMP in response to stimulation with PGD2.

REFERENCES Arimura A, Yasui K, Kishino J, Asanuma F, Hasegawa H, Kakudo S, Ohtani M, Arita H (2001). Prevention of allergic inflammation by a novel prostaglandin receptor antagonist, S-5751. J Pharmacol Exp Ther 298 (2), 411-9 Armstrong, R. A. 1996 Platelet prostanoid receptors. Pharmacol. Ther. 72: 171-191. Boie, Y., Sawyer, N., Slipetz, D.M., Metters, K.M., Abramovitz, M. 1995. Molecular cloning and characterization of the human prostanoid DP receptor. J. Biol. Chem. 270: 18910-18916. Brightling CE, Bradding P, Pavord ID, Wardlaw AJ (2003). New Insights into the role of the mast cell in asthma. Clin Exp Allergy 33, 550-556 Coleman, R.A. , Smith, W.L., Narumiya, S. 1994 VIII. International union of pharmacology classification of prostanoid receptors: properties, distribution, and structure of the receptors and their subtypes. Pharmacol. Rev. 46: 205-229. Doyle WJ, Boehm S, Skoner DP (1990) Physiologic responses to intranasal dose-response challenges with histamine, methacholine, bradykinin, and prostaglandin in adult volunteers with and without nasal allergy. J Allergy Clin Immunol. 86 (6 Pt 1), 924-35 Hirata, M., Kakizuka, A., Aizawa, M., Ushikubi, F., Narumiya, S. 1994 Molecular characterization of a mouse prostaglandin D receptor and functional expression of the cloned gene . 91: 11192-11196. Holgate S, Lackie P, Wilson S, Roche W, Davíes D. (2000) Bronchial Epithelium as a key Regulator of Airway Allergen Sensitization and Remodeling in Asthma. Am J Respir Crit Care Med. 162, 113-117 Ito, S., Narumiya, S. and Hayaishi, O. 1989 Prostaglandin D2: a biochemical perspective Pros. Leuko I am. Fatty Acids 37: 219-234. Lewis, RA, Soter NA, Diamond PT, Austen KF, Oates JA, Roberts LJ II (1982). Prostaglandin D2 generation after activation of rat and human mast cells with anti-IgE. J. Im-munol 129, 1627-1631. Matsuoka, T., Hirata, M., Tanaka, H., Takahashi, Y., Murata, T., Kabashima, K, Sugimoto, Y., Kobayashi, T., Ushikubi, F., Aze, Y., Eguchi , N., Urade, Y., Yoshida, N., Kimura, K, Mizoguchi, A., Honda, Y., Nagai, H., Narumiya, S. 2000 Prostaglandin D2 as a mediator of allergic asthma. Science 287: 2013-2017. Sambrook, et al., Eds. Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring Harbor Press, Cold Spring Harbor, N.Y., 1989. Roberts, L.J. II, Sweetman, B.J., Lewis, R.A. , Austin, K.F., Oates, J.A. 1980 Increased production of prostaglandin D2 in patients with systemic mastocytosis. N. Eng. J. Med. 303: 1400-1404. Wright, D.H., Nantel, F., Metters, K.M., Ford-Hutchinson, A.W. 1999 A novel biological role for prostaglandin D2 is suggested by distribution studies of the mouse DP prostanoid receptor. Eur. J. Pharmacol. 377: 101-115.

Claims (46)

1. CLAIMS 1.- An isolated nucleic acid molecule comprising the nucleic acid sequence of SEQ ID N0: 1. 2. The isolated nucleic acid molecule of claim 1, wherein the nucleic acid encodes the polypeptide of SEQ ID NO:
2. 2.
3. 3. The isolated nucleic acid molecule of claim 1, further comprising a detectable tracer.
4. 4. The isolated nucleic acid molecule of claim 3, wherein the detectable tracer comprises an enzyme, a radioactive isotope, or a chemical that emits fluorescence.
5. 5. The nucleic acid molecule isolated from claim 1, wherein the nucleic acid sequence is selected from the group consisting of RNA, synthetic RNA, genomic DNA, synthetic DNA and cDNA.
6. 6. An isolated nucleic acid molecule comprising a nucleic acid sequence that hybridizes to the nucleic acid sequence of SEQ ID NO: 1.
7. 7. - The isolated nucleic acid molecule of claim 6, wherein the nucleic acid sequence is hybridized under severe conditions.
8. 8. The isolated nucleic acid molecule of claim 7, in which the hybridization takes place in 6X SSC at about 45 ° C, followed by at least one wash in 0.2X SSC, and 0.1 SDS % at approximately 50-65 ° C.
9. 9. An isolated nucleic acid molecule comprising a nucleic acid encoding a polypeptide having the amino acid sequence of SEQ ID NO: 2.
10. 10. The nucleic acid molecule of claim 9, wherein, as a result of the degeneracy of the genetic code, the nucleic acid differs from the nucleic acid of SEQ ID N0: 1.
11. 11. An isolated nucleic acid molecule comprising a nucleic acid that is at least 65% identical to the nucleic acid of SEQ ID NO: 1.
12. 12. The isolated nucleic acid molecule of claim 11, wherein the nucleic acid is at least 75% identical to the nucleic acid of SEQ ID NO: 1.
13. 13. The nucleic acid molecule isolated from claim 12, wherein the nucleic acid is at least 85% identical to the nucleic acid of SEQ ID N0-.1.
14. 14. The isolated nucleic acid molecule of claim 12, wherein the nucleic acid is at least 95% identical to the nucleic acid of SEQ ID NO: 1.
15. 15. A recombinant polypeptide comprising the amino acid sequence of SEQ ID NO: 2.
16. 16. The recombinant polypeptide of claim 15 further comprising a detectable tracer.
17. 17. The recombinant polypeptide of claim 16, wherein the detectable tracer comprises an enzyme, a radioactive isotope, or a chemical that emits fluorescence.
18. 18. A recombinant polypeptide comprising an amino acid sequence that is at least 65% identical to the sequence of SEQ ID NO: 2 and that retains the function of the polypeptide of SEQ ID NO: 2.
19. 19.- The recombinant polypeptide of claim 18, wherein the amino acid sequence is at least 75% identical to the sequence of SEQ ID NO: 2.
20. 20. The recombinant polypeptide of claim 18, wherein the amino acid sequence is identical at least 85% to the sequence of SEQ ID NO: 2.
21. 21. - The recombinant polypeptide of claim 18, wherein the amino acid sequence is at least 95% identical to the sequence of SEQ ID NO: 2.
22. 22. An isolated nucleic acid molecule comprising a sequence of nucleic acid encoding the recombinant polypeptide of claim 18.
23. 23. An isolated nucleic acid molecule comprising a nucleic acid sequence encoding the recombinant polypeptide of claim 19.
24. 24.- An isolated nucleic acid molecule comprising a nucleic acid sequence encoding the recombinant polypeptide of claim 20.
25. 25.- An isolated nucleic acid molecule comprising a nucleic acid sequence encoding the recombinant polypeptide of claim 21.
26. 26.- An antibody specific for the recombinant polypeptide of claim 15.
27. 27.- The antibody of claim 26, wherein the antibody is selected from the group consisting of a monoclonal antibody, a polyclonal antibody, and a chimeric antibody.
28. 28. The antibody of claim 26, further comprising a detectable tracer.
29. 29. The antibody of claim 28, wherein a detectable tracer comprises an enzyme, a radioactive isotope, a chemical that emits fluorescence, or an antigenic peptide identifier that can be recognized by antibodies.
30. 30. An expression vector, the expression vector comprising the isolated nucleic acid molecule of claim 1 operatively associated with an expression control element.
31. 31. - The expression vector of claim 30, wherein the expression control element is selected from the group consisting of a constitutive regulatory sequence, a regulatory sequence with cellular specificity, and an inducible regulatory sequence.
32. 32. The expression vector of claim 30, wherein the expression control element is a promoter comprising an early immediate promoter of hCMV, an early SV40 promoter, an early adenovirus promoter, a precocious promoter of vaccinia, an early polyoma promoter, a SV40 late promoter, an adenovirus late promoter, a late vaccinia promoter, a late polyoma promoter, a lac system, a trp system, a TAC system, a TRC system, a region operator or major promoter of lambda phage, a control region of the fd bacteriophage coat protein, 3-phosphoglycerate kinase promoter, acid phosphatase promoter, or a yeast mating factor promoter a.
33. 33. A host cell transfected with the expression vector of claim 30.
34. 34.- The host cell of claim 33, wherein the host cell comprises a prokaryotic cell or a eukaryotic cell.
35. 35.- The host cell of claim 34, wherein the host cell comprises E. coli, Pseudomonas, Bacillus, Streptomyces, yeast, HCO, Rl.l, BW, LM, COSI, C0S7, BSC1, BSC40 cells, BMT10 or Sf9.
36. 36. An expression vector, the expression vector comprising the nucleic acid molecule isolated from claim 6 operatively associated with an expression control element.
37. 37.- A host cell transfected with the expression vector of claim 36.
38. 38. - An expression vector, the expression vector comprising the isolated nucleic acid molecule of claim 11 operatively associated with an expression control element.
39. 39.- A host cell transfected with the expression vector of claim 38.
40. 40.- An isolated nucleic acid molecule comprising antisense RNA complementary to a nucleic acid selected from the group consisting of a) nucleic acid of SEQ ID NO: l; b) a nucleic acid encoding the amino acid of SEQ ID NO: 2.
41. 41.- A transgenic non-human animal, the animal having a genome comprising a transgene comprising nucleic acid isolated from SEQ ID NO: 1.
42. 42. A method for producing the recombinant polypeptide of claim 15, the method comprising the steps of: a) culturing a host cell of claim 19 under conditions that provide expression of the recombinant polypeptide; and b) recovering the recombinant polypeptide.
43. 43.- A method of detecting a protein, the method comprising the steps of a) contacting the protein with an antibody according to claim 26; and b) evaluate the interaction between the antibody and the protein.
44. 44. A method for identifying an agonist of SEQ ID O: 2, the method comprising the steps of: a) contacting a potential agonist with a cell expressing SEQ ID NO: 2; and b) determining whether in the presence of the potential agonist the signaling activity of SEQ ID NO: 2 is increased relative to the activity of SEQ ID NO: 2 in the absence of the potential agonist.
45. 45.- A method for identifying an inverse agonist of SEQ ID NO: 2, the method comprising the steps of: a) contacting a potential inverse agonist with a cell expressing SEQ ID NO: 2; and b) determining whether in the presence of the potential inverse agonist the activity of SEQ ID NO: 2 decreases relative to the activity of SEQ ID NO: 2 in the absence of the potential inverse agonist, and decreases in the presence of an endogenous ligand or agonist.
46. 46. A method for identifying an antagonist of SEQ ID NO: 2, the method comprising the steps of: a) contacting a potential antagonist with a cell expressing SEQ ID NO: 2; and b) determining whether in the presence of the potential antagonist the signaling activity of SEQ ID NO: 2 decreases relative to the activity of SEQ ID NO: 2 in the presence of an endogenous ligand or agonist. SUMMARY A new member of the family of prostanoid receptors, a receptor for guinea pig prostaglandin D2, is described herein. The receptor is described, the nucleic acid that encodes it, and various uses for both. ATGTCCTTCTATCCCTGCAACACCACCGCCTCGGTACGGAGTGGGAACTC GGCGACGGTGGGCGGAGTGCTCTTCCGGGCCTCCTGGGCAACCTGC TGGCCCTCTGCTGGCACGCTCGGGGCTCGGGTCCTGCCGGCCGCGC CCGCCTCAGTCTTCTACGTGCTGGTGTGCGGCTTGACGGTCACAGA CCTGCTAGGCAAGTGCCTGGTGCGGTGGTGCTGGCTGCCTATGCGC AAAACCGGTCAGGGGACTGGCACCCGCGCAGGGCGACTCGCTGTGC CATTCGCCTTCATCATGTCCTTCTTTGGGCTCGCCTCGACGCTCCA GCTCTTATGGCCCTAGAGTGCTGGCTGTCCCTGGGACACCCCTTCT TCTACCGCACATCACTGTGCGCCGGGGCGTGCTCGTGGCGCCGGCT GTGGGCGCCTTCTGGCTTTCTGCGCGCTCCCCTTCGTGGGCTTCGG GAACTTTGTGCAGTACTGTCCCGGCACCTGGTGTTTCTTCCAGATGATCT CCGGGGACGACTCGCCGTCGGTGAAGGGCTACTCGGTGCTGTACTCCACC CTCATGGCGCTGTTGGTGCTCGCCATCGTGCTGTGCAACCTGGGCGCCAT GCGCAACCTCTACACCATGCACCCCTGCGACGGCACACGCGCTGCT GCTCCGGGACCGCGCGGGCGAGGCGTTTCCGCAATCCTTGGAGGAG CTGGACCACCTGCTGCTGCTGGCCCTCATGACCGTGCTCTTCACCATGTG CACTCTGCCGTTAGTTTATCGCGCTTACTATGGTTTAAGTCG AAGAGGCGACGACCTCCTTTGCGTTTTCTCTCTGTGATTTCA ATCGTGGACCCTTGGATCTTTATCATTTTCAGAACTTCAGTATTTCGGAT GTTTTTTCACAAGATTTTCATAAGACCTCTTCTTTACCGAAACTGGCACT GCCACTTCTACCAAACTAACGTGGAATCCAGTCTGTGA Figure 1