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WO2006070872A1 - Procede de mesure electrique et dispositif de mesure electrique d’une caracteristique et/ou d’un etat d’une membrane cellulaire - Google Patents

Procede de mesure electrique et dispositif de mesure electrique d’une caracteristique et/ou d’un etat d’une membrane cellulaire Download PDF

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Publication number
WO2006070872A1
WO2006070872A1 PCT/JP2005/024076 JP2005024076W WO2006070872A1 WO 2006070872 A1 WO2006070872 A1 WO 2006070872A1 JP 2005024076 W JP2005024076 W JP 2005024076W WO 2006070872 A1 WO2006070872 A1 WO 2006070872A1
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WO
WIPO (PCT)
Prior art keywords
current
cell
cell membrane
measuring
fluctuation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2005/024076
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English (en)
Japanese (ja)
Inventor
Makoto Taketani
Hiroaki Oka
Norihiro Katayama
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tohoku University NUC
Panasonic Holdings Corp
Original Assignee
Tohoku University NUC
Matsushita Electric Industrial Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tohoku University NUC, Matsushita Electric Industrial Co Ltd filed Critical Tohoku University NUC
Publication of WO2006070872A1 publication Critical patent/WO2006070872A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483—Physical analysis of biological material
    • G01N33/487—Physical analysis of biological material of liquid biological material
    • G01N33/48707—Physical analysis of biological material of liquid biological material by electrical means
    • G01N33/48728—Investigating individual cells, e.g. by patch clamp, voltage clamp

Definitions

  • the present invention relates to an electrical measurement method and an electrical measurement apparatus for at least one of characteristics and states of cell membranes.
  • Patent Document 1 WO00159447
  • Patent Document 2 US 6488829
  • Patent Document 3 US06315940
  • Patent Document 4 WO00125769
  • Non-patent literature 1 Neher E & Sakmann B (197 Rino Single cnannel currents recorded from m embraneof denervated frog muscle fibers. Nature 260: 799—802
  • Non-Patent Document 2 Hamill OP, Marty A, Neher E, Sakmann B & Sigworth FJ (1981) Impro ved patch-clamp techniques for high-resolution current recording from cells and cell -free membrane patches. Pflugers Arch 391: 85-100.
  • an object of the present invention is to provide an electrical measurement method and an electrical measurement apparatus that can measure at least one of the characteristics and state of a cell membrane faster, more accurately, and more easily than before.
  • the measurement method of the present invention is an electrical measurement method of at least one of the characteristics and state of a cell membrane, comprising preparing a measurement electrode, a reference electrode, and a plurality of cells.
  • the measurement electrode and each cell are electrically connected, and the reference electrode and each cell membrane surface are electrically connected, and in this state, a voltage is applied to the measurement electrode to both the electrodes.
  • This is an electrical measurement method for measuring fluctuations in the current flowing between them.
  • the measurement apparatus of the present invention is an electrical measurement apparatus for at least one of the characteristics and state of a cell membrane, comprising a container having a plurality of holes for holding and fixing cells, a measurement electrode, a reference electrode, An application unit that applies a voltage to the measurement electrode; a detection unit that detects a current flowing between the electrodes; and a measurement unit that measures fluctuations in the current; and the measurement electrode and each cell
  • the application means can connect the measurement electrode.
  • a voltage is applied, a current flowing between the electrodes is detected by the detection means, and the fluctuation of the current is detected by the measurement means. Is an electrical measuring device to be measured.
  • the measurement method and the measurement apparatus of the present invention measure fluctuations in current caused by at least one of the characteristics and state of the cell membrane for the entirety of a plurality of cells. As will be described later, this current fluctuation reflects the characteristics and state of the cell membrane of the plurality of cells as a whole. Therefore, according to the present invention, the cell membrane state and the like of a plurality of cells are measured simultaneously at the same time. Therefore, even if the success rate of the measurement of the cell membrane state and the like of individual cells is not 100%, a single measurement is performed. Thus, highly reliable information can be obtained. In addition, when measuring the current due to the state of the cell membrane, etc.
  • the present invention measures the fluctuation of the force current that requires conditions such as arranging electrodes for each cell and insulating the cells. Therefore, a pair of electrodes (measurement electrode and reference electrode) that do not need to insulate each cell can measure the cell membrane state of multiple cells, and it is necessary to apply strict measurement conditions such as current measurement. There is no. Therefore, according to the present invention, it is possible to measure at least one of the characteristics and state of the cell membrane faster, more accurately and more easily than the conventional method.
  • FIG. 1 (a) is a diagram showing an example of an electric circuit presumed to be formed inside and outside a cell
  • FIG. 1 (b) shows a simplified model of the electric circuit.
  • FIG. 2 is a diagram showing an example of an electric circuit presumed to be formed in a plurality of cells.
  • FIG. 3 is a cross-sectional view showing an example of a container constituting a part of the electrical measuring apparatus of the present invention.
  • FIG. 4 is a graph theoretically examined for the reproducibility of the number of cells per electrode and current amplitude in an example of the electrical measurement method of the present invention.
  • FIG. 5 is a block diagram showing an example of an electrical measuring apparatus according to the present invention.
  • FIG. 6 is a graph theoretically obtained dose response characteristics using the standard deviation of the current value at 20 cells in an example of the electrical measurement method of the present invention.
  • FIG. 7 is a diagram of a power spectrum in one embodiment of the electrical measurement method of the present invention.
  • the electrical measurement apparatus of the present invention preferably further includes a power spectrum measurement means for measuring a power spectrum of the current fluctuation.
  • the number of the plurality of cells is not particularly limited, and is a force determined appropriately according to various conditions.
  • the range is 2 to: LOO.
  • the characteristics and state of the cell membrane to be measured and measured include, for example, the characteristics and state of ion channels existing in the cell membrane.
  • the characteristics and states of the ion channel include at least one of the number of ion channels and the open / closed state of the ion channels.
  • the cells may be, for example, individually separated cells or cells existing in a tissue.
  • the fluctuation of the current may be measured before and after the chemical substance is administered to the cell.
  • the influence of the chemical substance on the cell membrane can be measured, and is useful, for example, in the development of pharmaceuticals.
  • the electrical measuring device of the present invention is preferably used for examining the influence of chemical substances on the cell membrane.
  • the container can be filled with an electrolyte solution, and the electrolyte solution can be used between the measurement electrode and each cell and between the reference electrode and each of the cells.
  • the cell membrane surface may be electrically connected.
  • the number of holes in the container is not particularly limited, and is a force determined appropriately depending on the number of cells to be measured, etc.
  • the range of 2 to: LOO. is there.
  • a feature of the present invention is that, for a plurality of cells that do not measure a membrane potential, a fluctuation in current that reflects the characteristics and state of the cell membrane is measured collectively for a single cell.
  • the fluctuation of the current of the plurality of cells is the sum of the fluctuations of the current of each cell. Then, by measuring the power spectrum of fluctuations in the membrane current of multiple cells and analyzing it, the characteristics and state of the cell membrane can be evaluated in detail. The rationale is as follows.
  • Figure 1 shows an equivalent circuit model when one cell is in a state of forming a seal in the device hole.
  • the model parameters are summarized in the table described later.
  • the seal resistance R is sufficiently large (>> 100 M ⁇ ) and the resistance R of the cell surface in contact with the device is small enough ( ⁇ 20 M ⁇ )
  • take the appropriate reference voltage ⁇ 20 M ⁇
  • the part of the circuit in Fig. 1 (a) excluding the capacitance component C can be simplified as shown in Fig. 1 (b). Die of this system
  • Namitas is shown by the following formula (1).
  • FIG. 2 shows an equivalent circuit model of an eHTS device system using multiple cells.
  • This system has a structure in which a device hole system that forms a seal with each cell is connected in parallel. If the number of cells is N, the observed current I is given by the following equation (2).
  • the current fluctuation in the steady state recorded in the voltage-clamped mode is the conductance g that accompanies the switching fluctuation of the ion channel.
  • the bandwidth of the observed signal is limited by the ch m acc filter characteristics, which consists of this resistance component, cell membrane capacitance component C, and access resistance R.
  • the time constant of this system is given by the following equation (4).
  • the conductance change is proportional to the change in the number of open channels. For this reason, it is possible to evaluate the fluctuation of the number of aperture channels by performing spectrum analysis of the membrane current fluctuation signal.
  • Membrane conductance is expressed as the membrane conductance g
  • a channel having a potential dependency is included in the membrane potential V force S. Opening m
  • the membrane current is also a stochastic process. As shown above, the minute change component of the membrane current is proportional to the fluctuation of the number of open channels. Therefore, the power spectrum of the membrane current fluctuation component (difference from the average value, i (t)) is proportional to the power spectrum of channel fluctuation P. Therefore, these are equated below.
  • the observed current in an eHTS device in which a plurality of cell lines form a parallel circuit is the sum of the cell membrane currents.
  • the fluctuation z (t) of the observed current can be expressed by the following equation (8).
  • S ( ⁇ ) and S ( ⁇ ) are cross spectra of x and y, and are represented by the following formula (15).
  • the power spectrum ( ⁇ ) of the total current I which is the sum of ⁇ cell membrane currents Ij, can be assumed that there is no correlation between the current fluctuations. Equal to ( ⁇ ). That is, it can be expressed as the following formula (18).
  • V Command potential (determined by the experimenter)
  • V Intracellular potential (membrane potential)
  • FIG. 3 is a cross-sectional view of the container 1 used for measurement.
  • the material of the container 1 include single crystal substrates such as silicon, gallium arsenide, and quartz, as well as glass, quartz, and resin. Various substrate materials are used.
  • the container body 11 is partitioned vertically by an internal force cutting plate 11A, and a plurality of holes 14 are formed in the partition plate 11A. Cells 17 are retained and fixed.
  • the diameter of the hole 14 is determined optimally depending on the size of the cell 17. For example, when the measurement target is HEK cells, the diameter of the hole 14 is usually 0.5 to 10 ⁇ m. Meters, preferably 1 to 5 micrometers in diameter.
  • the optimum number of pores 14 is influenced by the activity of the cell 17 to be measured, the degree of adsorption of the cells 17 to the pore 14, etc., and is the most efficient measurement by the measurement method described later. It is decided so.
  • one measurement electrode 12 is disposed on the lower surface of the partition plate 11A. In the measurement electrode 12, holes 15 are formed in portions corresponding to the holes 14 of the partition plate. Yes.
  • the interior of the container body 11 that is partitioned up and down is filled with the electrolyte solution 16.
  • a single reference electrode 13 is disposed on the top of the container body 11 so as to enter the electrolyte solution 16.
  • a conductive material such as gold, silver, copper, aluminum, stainless steel, chromium, titanium, or the like is used.
  • a portion of these conductive materials is provided with salty silver. It is that you are. This makes it possible to measure the potential change of the electrolyte solution 16 more accurately.
  • the shape and size of these electrodes are not particularly limited. As shown in the measurement electrode 12 shown in the figure, the partition plate 11A can be simply immersed in the electrolyte solution 16 as in the reference electrode 13 in FIG. May be formed in close contact with the inner wall of the container 1.
  • the electrode material such as gold, silver, copper, aluminum, stainless steel, chromium, titanium, silver chloride, etc. is deposited, sputtered, plated, etc.
  • An electrode may be formed on the surface.
  • the cell membrane in the portion located in the hole 14 of the partition plate is partially broken. Therefore, the measurement electrode 12 and the inside of the cell 17 are electrically connected by the electrolyte solution 16. Further, the cell 17 membrane surface and the reference electrode 13 are electrically connected by the electrolyte solution 16.
  • the measurement electrode 12 and the reference electrode 13 are connected to a current Z voltage conversion circuit, an AZD conversion circuit, a DZA conversion circuit, a CPU, a display device, and the like via a connector.
  • a current Z voltage conversion circuit an AZD conversion circuit
  • a DZA conversion circuit a DZA conversion circuit
  • CPU a display device
  • the like a connector
  • FIG. 5 is a schematic diagram of a measuring apparatus used for measurement.
  • the electrical measuring device 18 includes a control unit 19, a D / A conversion circuit 20 connected thereto, a current Z voltage conversion circuit 21, an A / D conversion circuit 22 and a solution driving unit 23, a mounting unit 24, and a stimulation signal.
  • a grant unit 26 is provided.
  • 1 indicates the container.
  • the measurement of the current fluctuation of the cell membrane using this apparatus is performed, for example, as follows. That is, first, the container 1 is placed on the placement unit 24. The placement unit 24 can hold the placed container 1 at a predetermined temperature, gas concentration, humidity, and atmospheric pressure. Next, the isolated cell 17 is introduced from the upper surface of the container 1.
  • the control unit 19 detects and records the current flowing between the electrodes 12 and 13 of the container 1 based on the signal input from the current Z voltage conversion circuit.
  • the control unit 19 controls the stimulation signal applying unit 26 via the D / A conversion circuit 20 and the current Z voltage conversion circuit 21 based on the set stimulation conditions.
  • This current reflects the cell membrane state of the plurality of cells 17 as a whole.
  • This current is detected by the measurement electrode 12 and the reference electrode 13, and is input to the control unit 19 through the current Z voltage conversion circuit 21 and the AZD conversion circuit 22, and is measured as current fluctuation in the CPU. Power spectrum analysis. The analysis result is displayed on the display device.
  • the current fluctuation reflects the state of the entire cell membrane of a plurality of cells, for example, the number of ion channels, opening / closing, and the like.
  • the solution driving unit 23 discharges the electrolyte solution 16 inside the container body 11, and the tank has a function of injecting the electrolyte solution 16 into the container body 11, and is driven by the control unit 19 as necessary.
  • the graph in Fig. 4 shows a theoretical study of the reproducibility of the number of cells per electrode and the current amplitude. This graph shows the number of cells measured together when the success rate of measurement is not 1.0 (100%) due to factors such as hole failure, insufficient seal, unstable baseline, and insufficient ion channel expression. Increasing the value indicates that the coefficient of variation decreases, that is, the reproducibility increases.
  • the graph in Fig. 6 is a theoretical calculation of dose response characteristics using the standard deviation of the current value for 20 cells, and shows the simulation of noise current characteristics when a drug is applied to cells. It is a graph. Membrane current fluctuations were simulated when an open channel blocker was applied to a cell model incorporating a membrane voltage-gated ion channel, and the relationship between the block force concentration and the standard deviation (SD) of the noise current was measured in a steady state. evaluated. The dissociation constant of the block force was 10 M. SD has a maximum when the drug concentration is the dissociation constant. As shown in the figure, by utilizing this characteristic, it is possible to estimate the dissociation constant of the drug from the noise current.
  • Example 1 [0061] In the container 1 shown in FIG. 3, the number of the holes 14 was two, and the current fluctuation was actually measured using the electrical measuring device shown in FIG. 5 (FIG. 5). The following operation was performed at 25 ° C.
  • the inner electrolyte solution (KC1 130 mM, MgCl 1 mM, EGTA 5 mM, ATP 5)
  • the upper surface of the device (vessel 1 upper side) is the outer electrolyte solution (NaCl 137 mM, KC1 4 mM, CaCl 1.8 mM, MgCl 1 mM, glucose 10 mM, HEPES
  • HEK cells in which hERG channels were steadily expressed were isolated by pipetting in an external solution in a separate container and then placed on the upper surface of the device.
  • negative pressure up to 530mmHg
  • the sealing resistance between the device and cells was increased.
  • the inner electrolyte solution on the lower surface of the device was replaced with a solution containing -statin (nystatin concentration 250 g / ml) to construct perforations with nystatin in the cell membrane.
  • hERG-expressing HEK cells were first fixed at ⁇ 80 mV using an EPC-10 amplifier (HEKA), then the fixed voltage was raised to OmV for 6 seconds. Fluctuations were measured. The measured current fluctuation was digitally sampled at 10 kHz (PATCHMASTER software, manufactured by HEKA), and the power spectrum was obtained by fast Fourier transform of the data for the last 2 seconds (Origin 7.0). Next, the hERG channel inhibitor E-4031 (manufactured by Sigma) is placed in the outer electrolyte solution on the upper surface of the device to a final concentration of 1M, and the voltage fluctuation is similarly fixed to measure the current fluctuation. The power spectrum was determined. These power spectra are shown in the graph of Fig. 7.
  • the electrical measurement method and the electrical measurement device for at least one of the characteristics and states of the cell membrane of the present invention summarize the fluctuations in current caused by the characteristics and states of the cell membranes of a plurality of cells. Therefore, electrical measurement of cell membrane state and the like is possible at high speed, accurately and easily. Therefore, the electrical measurement method and electrical measurement apparatus of the present invention are applicable to all fields for analyzing characteristics and states of cell membranes such as ion channel states. For example, it is useful in fields such as biology, medicine, pharmacy, and agriculture, and is particularly suitable for the development of pharmaceuticals.

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  • Health & Medical Sciences (AREA)
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  • Investigating Or Analysing Biological Materials (AREA)
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Abstract

L’invention concerne un procédé de mesure capable d’effectuer une mesure électrique rapide, précise et simple des états de membranes cellulaires. Le procédé de mesure électrique des états de membranes cellulaires comprend l’étape consistant à utiliser une électrode de mesure (12), une électrode de référence (13) et une pluralité de cellules (17), reliant électriquement l’électrode de mesure (12) aux parties intérieures des cellules (17) respectives et reliant électriquement l’électrode de référence (13) à des surfaces des cellules (17) respectives, et, dans ces conditions, l’étape consistant à appliquer une tension à l’électrode de mesure (12) pour mesurer la variation d’un courant circulant entre les deux électrodes (12, 13). La variation d’un courant au niveau de la pluralité de cellules est égale à la variation d’un courant au niveau de chaque cellule. L’analyse du spectre de puissance de cette variation de courant permet d’évaluer l’état d’une membrane cellulaire.
PCT/JP2005/024076 2004-12-28 2005-12-28 Procede de mesure electrique et dispositif de mesure electrique d’une caracteristique et/ou d’un etat d’une membrane cellulaire Ceased WO2006070872A1 (fr)

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JP2004-380245 2004-12-28
JP2004380245A JP2006184207A (ja) 2004-12-28 2004-12-28 細胞膜の特性および状態の少なくとも一方の電気的測定方法および電気的測定装置

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010527440A (ja) * 2007-05-04 2010-08-12 テセラ， エルエルシー パッチクランプシステムにおける使用のためのサブシステムおよび方法

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Publication number Priority date Publication date Assignee Title
JP6308134B2 (ja) 2012-12-27 2018-04-11 ソニー株式会社 細胞分析システム、細胞分析プログラム及び細胞分析方法
JP6942925B2 (ja) 2013-11-08 2021-09-29 ソニーグループ株式会社 細胞分析システム、細胞分析プログラム及び細胞分析方法

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JP2002518678A (ja) * 1998-06-12 2002-06-25 セネス リミティド 高処理量スクリーン
WO2002055653A1 (fr) * 2001-01-09 2002-07-18 Matsushita Electric Industrial Co., Ltd. Dispositif de mesure du potentiel extracellulaire, procede permettant de mesurer le potentiel extracellulaire a l'aide dudit dispositif et appareil utilise pour cribler rapidement le medicament apporte par ce dernier
JP2003511699A (ja) * 1999-10-08 2003-03-25 エンエムイー ナトゥヴィッセンシャフトリヘス ウント メディツィニシェス インスティテュート アン デル ウニヴェルシタト ティユービンゲン 液体環境内にある細胞の測定を行なう方法および装置
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JP2002518678A (ja) * 1998-06-12 2002-06-25 セネス リミティド 高処理量スクリーン
JP2003511668A (ja) * 1999-10-01 2003-03-25 ソフィオン・バイオサイエンス・アクティーゼルスカブ イオンチャネルの電気生理的性質を測定及び／または監視するための基体及び方法
JP2003511699A (ja) * 1999-10-08 2003-03-25 エンエムイー ナトゥヴィッセンシャフトリヘス ウント メディツィニシェス インスティテュート アン デル ウニヴェルシタト ティユービンゲン 液体環境内にある細胞の測定を行なう方法および装置
WO2002055653A1 (fr) * 2001-01-09 2002-07-18 Matsushita Electric Industrial Co., Ltd. Dispositif de mesure du potentiel extracellulaire, procede permettant de mesurer le potentiel extracellulaire a l'aide dudit dispositif et appareil utilise pour cribler rapidement le medicament apporte par ce dernier

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EBINA Y. ET AL.: "Risan Jikan Markov Chain Model ni yoru Makudenryu Yuragi no Power Spectrum Mitsudoshiki. (Power Spectrum Densisty Equation of Flustuating Membrane Current Based on Discrete Time Markov Chain Model 'Analysis of Ion Channels with 2,3 States')", THE TRANSACTIONS OF THE INSTITUTE OF ELECTRONICS, INFORMATION AND COMMUNICATION ENGINEERS D-II, vol. J72-D-II, no. 11, 25 November 1989 (1989-11-25), pages 1926 - 1934, XP003002099 *

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Publication number Priority date Publication date Assignee Title
JP2010527440A (ja) * 2007-05-04 2010-08-12 テセラ， エルエルシー パッチクランプシステムにおける使用のためのサブシステムおよび方法

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