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Review ArticleReview Article

Cell Volume-Activated and Volume-Correlated Anion Channels in Mammalian Cells: Their Biophysical, Molecular, and Pharmacological Properties

Yasunobu Okada, Toshiaki Okada, Kaori Sato-Numata, Md. Rafiqul Islam, Yuhko Ando-Akatsuka, Tomohiro Numata, Machiko Kubo, Takahiro Shimizu, Ranohon S. Kurbannazarova, Yoshinori Marunaka and Ravshan Z. Sabirov
Yoshihiro Ishikawa, ASSOCIATE EDITOR
Pharmacological Reviews January 2019, 71 (1) 49-88; DOI: https://doi.org/10.1124/pr.118.015917
Yasunobu Okada
Departments of Physiology and Systems Bioscience (Y.O.) and Molecular Cell Physiology (Y.M.), Kyoto Prefectural University of Medicine, Kyoto, Japan; Division of Cell Signaling, National Institute for Physiological Sciences, Okazaki, Japan (Y.O., T.O., M.R.I., M.K., R.Z.S.); Department of Physiology, School of Medicine, Fukuoka University, Fukuoka, Japan (K.S.-N., T.N.); Department of Cell Physiology, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan (Y.A.-A.); Department of Pharmaceutical Physiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (T.S.); Laboratory of Molecular Physiology, Institute of Bioorganic Chemistry, Academy of Sciences of Uzbekistan, Tashkent, Uzbekistan (R.S.K., R.Z.S.); and Research Institute for Clinical Physiology, Kyoto Industrial Health Association, Kyoto, Japan (Y.M.)
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Toshiaki Okada
Departments of Physiology and Systems Bioscience (Y.O.) and Molecular Cell Physiology (Y.M.), Kyoto Prefectural University of Medicine, Kyoto, Japan; Division of Cell Signaling, National Institute for Physiological Sciences, Okazaki, Japan (Y.O., T.O., M.R.I., M.K., R.Z.S.); Department of Physiology, School of Medicine, Fukuoka University, Fukuoka, Japan (K.S.-N., T.N.); Department of Cell Physiology, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan (Y.A.-A.); Department of Pharmaceutical Physiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (T.S.); Laboratory of Molecular Physiology, Institute of Bioorganic Chemistry, Academy of Sciences of Uzbekistan, Tashkent, Uzbekistan (R.S.K., R.Z.S.); and Research Institute for Clinical Physiology, Kyoto Industrial Health Association, Kyoto, Japan (Y.M.)
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Kaori Sato-Numata
Departments of Physiology and Systems Bioscience (Y.O.) and Molecular Cell Physiology (Y.M.), Kyoto Prefectural University of Medicine, Kyoto, Japan; Division of Cell Signaling, National Institute for Physiological Sciences, Okazaki, Japan (Y.O., T.O., M.R.I., M.K., R.Z.S.); Department of Physiology, School of Medicine, Fukuoka University, Fukuoka, Japan (K.S.-N., T.N.); Department of Cell Physiology, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan (Y.A.-A.); Department of Pharmaceutical Physiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (T.S.); Laboratory of Molecular Physiology, Institute of Bioorganic Chemistry, Academy of Sciences of Uzbekistan, Tashkent, Uzbekistan (R.S.K., R.Z.S.); and Research Institute for Clinical Physiology, Kyoto Industrial Health Association, Kyoto, Japan (Y.M.)
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Md. Rafiqul Islam
Departments of Physiology and Systems Bioscience (Y.O.) and Molecular Cell Physiology (Y.M.), Kyoto Prefectural University of Medicine, Kyoto, Japan; Division of Cell Signaling, National Institute for Physiological Sciences, Okazaki, Japan (Y.O., T.O., M.R.I., M.K., R.Z.S.); Department of Physiology, School of Medicine, Fukuoka University, Fukuoka, Japan (K.S.-N., T.N.); Department of Cell Physiology, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan (Y.A.-A.); Department of Pharmaceutical Physiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (T.S.); Laboratory of Molecular Physiology, Institute of Bioorganic Chemistry, Academy of Sciences of Uzbekistan, Tashkent, Uzbekistan (R.S.K., R.Z.S.); and Research Institute for Clinical Physiology, Kyoto Industrial Health Association, Kyoto, Japan (Y.M.)
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Yuhko Ando-Akatsuka
Departments of Physiology and Systems Bioscience (Y.O.) and Molecular Cell Physiology (Y.M.), Kyoto Prefectural University of Medicine, Kyoto, Japan; Division of Cell Signaling, National Institute for Physiological Sciences, Okazaki, Japan (Y.O., T.O., M.R.I., M.K., R.Z.S.); Department of Physiology, School of Medicine, Fukuoka University, Fukuoka, Japan (K.S.-N., T.N.); Department of Cell Physiology, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan (Y.A.-A.); Department of Pharmaceutical Physiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (T.S.); Laboratory of Molecular Physiology, Institute of Bioorganic Chemistry, Academy of Sciences of Uzbekistan, Tashkent, Uzbekistan (R.S.K., R.Z.S.); and Research Institute for Clinical Physiology, Kyoto Industrial Health Association, Kyoto, Japan (Y.M.)
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Tomohiro Numata
Departments of Physiology and Systems Bioscience (Y.O.) and Molecular Cell Physiology (Y.M.), Kyoto Prefectural University of Medicine, Kyoto, Japan; Division of Cell Signaling, National Institute for Physiological Sciences, Okazaki, Japan (Y.O., T.O., M.R.I., M.K., R.Z.S.); Department of Physiology, School of Medicine, Fukuoka University, Fukuoka, Japan (K.S.-N., T.N.); Department of Cell Physiology, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan (Y.A.-A.); Department of Pharmaceutical Physiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (T.S.); Laboratory of Molecular Physiology, Institute of Bioorganic Chemistry, Academy of Sciences of Uzbekistan, Tashkent, Uzbekistan (R.S.K., R.Z.S.); and Research Institute for Clinical Physiology, Kyoto Industrial Health Association, Kyoto, Japan (Y.M.)
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Machiko Kubo
Departments of Physiology and Systems Bioscience (Y.O.) and Molecular Cell Physiology (Y.M.), Kyoto Prefectural University of Medicine, Kyoto, Japan; Division of Cell Signaling, National Institute for Physiological Sciences, Okazaki, Japan (Y.O., T.O., M.R.I., M.K., R.Z.S.); Department of Physiology, School of Medicine, Fukuoka University, Fukuoka, Japan (K.S.-N., T.N.); Department of Cell Physiology, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan (Y.A.-A.); Department of Pharmaceutical Physiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (T.S.); Laboratory of Molecular Physiology, Institute of Bioorganic Chemistry, Academy of Sciences of Uzbekistan, Tashkent, Uzbekistan (R.S.K., R.Z.S.); and Research Institute for Clinical Physiology, Kyoto Industrial Health Association, Kyoto, Japan (Y.M.)
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Takahiro Shimizu
Departments of Physiology and Systems Bioscience (Y.O.) and Molecular Cell Physiology (Y.M.), Kyoto Prefectural University of Medicine, Kyoto, Japan; Division of Cell Signaling, National Institute for Physiological Sciences, Okazaki, Japan (Y.O., T.O., M.R.I., M.K., R.Z.S.); Department of Physiology, School of Medicine, Fukuoka University, Fukuoka, Japan (K.S.-N., T.N.); Department of Cell Physiology, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan (Y.A.-A.); Department of Pharmaceutical Physiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (T.S.); Laboratory of Molecular Physiology, Institute of Bioorganic Chemistry, Academy of Sciences of Uzbekistan, Tashkent, Uzbekistan (R.S.K., R.Z.S.); and Research Institute for Clinical Physiology, Kyoto Industrial Health Association, Kyoto, Japan (Y.M.)
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Ranohon S. Kurbannazarova
Departments of Physiology and Systems Bioscience (Y.O.) and Molecular Cell Physiology (Y.M.), Kyoto Prefectural University of Medicine, Kyoto, Japan; Division of Cell Signaling, National Institute for Physiological Sciences, Okazaki, Japan (Y.O., T.O., M.R.I., M.K., R.Z.S.); Department of Physiology, School of Medicine, Fukuoka University, Fukuoka, Japan (K.S.-N., T.N.); Department of Cell Physiology, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan (Y.A.-A.); Department of Pharmaceutical Physiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (T.S.); Laboratory of Molecular Physiology, Institute of Bioorganic Chemistry, Academy of Sciences of Uzbekistan, Tashkent, Uzbekistan (R.S.K., R.Z.S.); and Research Institute for Clinical Physiology, Kyoto Industrial Health Association, Kyoto, Japan (Y.M.)
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Yoshinori Marunaka
Departments of Physiology and Systems Bioscience (Y.O.) and Molecular Cell Physiology (Y.M.), Kyoto Prefectural University of Medicine, Kyoto, Japan; Division of Cell Signaling, National Institute for Physiological Sciences, Okazaki, Japan (Y.O., T.O., M.R.I., M.K., R.Z.S.); Department of Physiology, School of Medicine, Fukuoka University, Fukuoka, Japan (K.S.-N., T.N.); Department of Cell Physiology, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan (Y.A.-A.); Department of Pharmaceutical Physiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (T.S.); Laboratory of Molecular Physiology, Institute of Bioorganic Chemistry, Academy of Sciences of Uzbekistan, Tashkent, Uzbekistan (R.S.K., R.Z.S.); and Research Institute for Clinical Physiology, Kyoto Industrial Health Association, Kyoto, Japan (Y.M.)
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Ravshan Z. Sabirov
Departments of Physiology and Systems Bioscience (Y.O.) and Molecular Cell Physiology (Y.M.), Kyoto Prefectural University of Medicine, Kyoto, Japan; Division of Cell Signaling, National Institute for Physiological Sciences, Okazaki, Japan (Y.O., T.O., M.R.I., M.K., R.Z.S.); Department of Physiology, School of Medicine, Fukuoka University, Fukuoka, Japan (K.S.-N., T.N.); Department of Cell Physiology, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Japan (Y.A.-A.); Department of Pharmaceutical Physiology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan (T.S.); Laboratory of Molecular Physiology, Institute of Bioorganic Chemistry, Academy of Sciences of Uzbekistan, Tashkent, Uzbekistan (R.S.K., R.Z.S.); and Research Institute for Clinical Physiology, Kyoto Industrial Health Association, Kyoto, Japan (Y.M.)
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Yoshihiro Ishikawa
Roles: ASSOCIATE EDITOR
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  • Fig. 1.
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    Fig. 1.

    Primary actions of opening of anion channels in either a KCC-dominant case (A) or an NKCC-dominant case (B) (see the text for details).

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    Fig. 2.

    VSOR and Maxi-Cl currents in human monocytic U937 cells. (A) Macroscopic whole-cell VSOR currents recorded from U937 cells after osmotic swelling (left) and the corresponding current-to-voltage relationship (right). Experimental conditions, other than the cell line used, are the same as reported previously (Sabirov et al., 2001; Kurbannazarova et al., 2011). (B) Single VSOR currents recorded from cell-attached patches on preswollen cells. Holding membrane potentials are indicated on the left of each trace. The right panel shows the unitary current-voltage relationship. The calculated slope conductance is 84.5 ± 5.8 and 14.7 ± 2.4 pS for outward and inward currents, respectively. Experimental conditions, other than the cell line used, are the same as reported previously (Ternovsky et al., 2004; Kurbannazarova et al., 2011) with 100 mM TEACl-pipette and 100 mM KCl-bath solutions. (C) Activation of Maxi-Cl currents in U937 cells. (Left) Voltage- and time-dependent inactivation of the steady-state membrane current as observed in excised macropatches in response to voltage pulses (500 milliseconds) from a holding potential at 0 to ±50 mV in 10-mV increments. The pipette and bath solutions were normal Ringer’s solution. (Right) Single-channel I-V relationships for maxi-anion channel events recorded. Each symbol represents the mean ± S.E. (vertical bar). The solid line is a linear fit with a slope conductance of 445.3 ± 9.6 pS. Experimental conditions, other than the cell line used, are the same as reported previously (Islam et al., 2012).

  • Fig. 3.
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    Fig. 3.

    Cl− current amplitudes plotted against [ATP]i, [Mg2+]i, and voltages. Each symbol represents the mean current of four different Intestine 407 cells. Vertical bars represent the S.E. (A) [ATP]i dependence of the peak Cl− currents measured at +40 mV at a fixed [Mg2+]i (1 mM). Data points were fitted by the following equation: I = Imax([ATP]i/EC50)/{1 + ([ATP]i/EC50)}. (B) [Mg2+]i dependence of the peak Cl− currents measured at +40 mV at a fixed [ATP]i (0.1 or 0.01 mM). Data points were fitted by the following equation: I = Imax/{1 + ([Mg2+]i/IC50)}. (C) Current-voltage relationships. Normalized peak Cl− currents (IV/I+40-mV) were measured at different [Mg2+]i and fixed [ATP]i. Mg2+ did not change the reversal potential, indicating that the Mg2+ effect is independent of voltage and that Mg2+ cannot permeate the channel. Experimental conditions are the same as reported previously (Oiki et al., 1994).

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    Fig. 4.

    Dual mechanisms for VSOR activation. The bottom half represents the membrane unfolding-induced (type A) mechanism, which takes place upon cell swelling, and the top half represents the oxidation-induced (type B) mechanism, which takes place upon receptor stimulation (see the text for details and other abbreviations). BKR, bradykinin receptor; DAG, diacylglycerol; Gq, heterotrimeric G protein that activates phospholipase C; IP3, inositol trisphosphate; mGluR, metabotropic glutamate receptor; P2YR, P2Y purinergic receptor; PKC, protein kinase C; PLC, phospholipase C; ROC, receptor-operated channel; SOC, store-operated channel.

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    Fig. 5.

    Effects of H2O2 stimulation on the subcellular localization of ACTN4 and molecular interaction between ACTN4 and ABCF2. (A and B) Accumulation of ACTN4, but not ABCF2, in the RIPA-insoluble fraction with 0.5 mM H2O2 stimulation. Five micrograms of RIPA-soluble and RIPA-insoluble fractions of the 100,000g pellet prepared from the cells transiently overexpressing ACTN4/FLAG and ABCF2/HA were subjected to SDS-PAGE and immunoblotting with anti-FLAG M2 mAb and anti-HA and anti–caveolin-1 antibodies. (A) Immunoblots. ACTN4/FLAG, ABCF2/HA, and caveolin-1 were detected. Molecular weight markers (in kilodaltons) are indicated on the left. (B) Densitometric analysis of the immunoblot data shown in (A). The ratio of the ACTN4/FLAG contents (normalized with caveolin-1 content) in the presence of 0.5 mM H2O2 to that in the absence of 0.5 mM H2O2 is plotted. *P < 0.05 (significant difference between the data from cells with or without H2O2 stimulation). (C and D) H2O2 stimulation enhances the interaction between ACTN4 and ABCF2 in the RIPA-insoluble fraction. (C) RIPA-soluble and RIPA-insoluble proteins from the 100,000g pellets were immunoprecipitated using anti-FLAG M2 mAb and were immunoblotted with anti-FLAG mAb and anti-HA antibody (right). Transfected ACTN4/FLAG and ABCF2/HA were shown in the input (left). (D) Densitometric analysis of the immunoblot data shown in (C). The ratio of the coprecipitated ABCF2/HA content (normalized with the precipitated ACTN4/FLAG content) with H2O2 stimulation (black columns) to that of control (white columns) is plotted. *P < 0.05 (significant difference between the data from cells with or without H2O2 stimulation). Experimental conditions are the same as reported previously (Ando-Akatsuka et al., 2012). HA, hemagglutinin; IB, immunoblotted; IP, immunoprecipitated; mAb, monoclonal antibody; RIPA, radioimmunoprecipitation assay buffer.

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    Fig. 6.

    Effects of NOX expression on VSOR currents in HEK293T cells. (A) Representative VSOR whole-cell currents elicited by step pulses from −100 to +100 mV in 20-mV increments during application of hypotonic (83% osmolality) solution in vector-transfected cells (upper panel) and NOX1-transfected cells (lower panel). (B) Mean VSOR currents recorded at +100 and −100 mV in vector-, NOX1-, NOX2-, NOX4-, and NOX5-transfected cells (n = 5–14). Experimental conditions are the same as reported previously (Okada et al., 2009a; Ando-Akatsuka et al., 2002).

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    Fig. 7.

    Strategy adopted in our study for molecular identification of the core component of Maxi-Cl. By performing bleb membrane proteomics followed by gene silencing and disruption, mutagenesis, pharmacology, heterologous expression, and recombinant protein reconstitution, SLCO2A1 protein was identified as a core component of the ATP-conductive Maxi-Cl channel (see the text and Sabirov et al., 2017 for details). LC, liquid chromatography; MS/MS, tandem mass spectrometry.

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    Fig. 8.

    Dual modes of SLCO2A1 functions as a transporter, PGT (left), and an ATP-permeable maxi-anion channel, Maxi-Cl (right).

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    Fig. 9.

    Chemical structures of some VSOR blockers. (A) Etacrynic acid derivatives. The blue dashed line depicts the 2,3-dichlorophenoxy fragment, which is identical for all of these molecules. The red dashed line delineates a fragment (short-chain oxy-carbonic acid combined with chlorinated cyclopentyl-oxo-indanyl) common for VSOR blockers (see the text for details) but not for etacrynic acid. (B) VSOR blockers that have two aromatic rings connected with a chain of one to four atoms (carbon, nitrogen, or mixed). The blue dashed lines mark the first aromatic ring (see the text for details). IAA-94, indanyloxyacetic acid 94.

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    Fig. 10.

    Voltage-dependent inhibition by DIDS of volume-sensitive outwardly rectifying Cl− currents in human cervical carcinoma HeLa cells. (A) Representative current traces before and after application of DIDS. Step pulses were applied from −100 to +100 mV in 20-mV increments, with a prepulse of −100 mV and a postpulse of −60 mV. (B) Concentration dependence of DIDS on the currents recorded at +100 mV (filled circles) and −100 mV (open circles) (n = 3–6). The IC50 values at +100 and −100 mV were 22.7 and 88.5 µM, respectively. Experimental conditions are the same as reported previously (Shimizu et al., 2004).

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    Fig. 11.

    Pharmacological profile of Maxi-Cl currents in patches excised from C127 cells. All of the columns represent the mean currents recorded at +25 mV. (A) Inhibitory effects of extracellular application of Gd3+ (50 μM) and intracellular application of arachidonic acid (20 μM). (B) Insensitivity to a VSOR blocker, DCPIB (10 μM), added from the intracellular or extracellular side. (C) Insensitivity to pannexin hemichannel antagonists, probenecid (1 mM) and 10Panx1 (8 μg/ml), added to the extracellular (pipette) solution. (D) Insensitivity to gap junction antagonists, CBX (100 μM), 1-octanol (2 mM), and GAP27 (4 μg/ml), added to the extracellular (pipette) solution. Experimental conditions, other than the cell line used, are the same as reported previously (Islam et al., 2012; Sabirov et al., 2017). AA, arachidonic acid; Probe, probenecid.

  • Fig. 12.
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    Fig. 12.

    Cd2+ insensitivity of Maxi-Cl (A) and ASOR (B) currents. (A) Representative Maxi-Cl currents recorded in inside-out patch membranes excised from C127 cells in the absence (control) and presence (+Cd2+) of 1 mM Cd2+ added to the extracellular (pipette) solution during application of step pulses from 0 to ±50 mV in 10-mV increments (protocol shown at the top). The bottom panel shows mean (± S.E.M.) NPo values measured at +25 mV in the absence and presence of Cd2+. There was no significant difference (at P > 0.05) between the two values. Experimental conditions are the same as reported previously (Islam et al., 2012; Sabirov et al., 2017). (B) Whole-cell ASOR currents recorded in HeLa cells in the absence and presence of 1 mM Cd2+ added to the bath solution. The upper panel shows whole-cell currents before (pH 7.5) and during (pH 4.5) exposure to acidic bath solution in the absence and presence of Cd2+. The currents were elicited by application of alternating pulses from 0 to ±40 mV or of step pulses (at a, b, and c) from −100 to +100 mV in 20-mV increments. The middle panel shows expanded traces of current responses (at a, b, and c) to the step pulses. The bottom panels show I-V relationships for the whole-cell current densities at pH 7.5 (squares) and pH 4.5 in the absence (circles) and presence (triangles) of Cd2+. There was no significant difference (at P > 0.05) between the circles and triangles at given voltages. Experimental conditions are the same as reported previously (Sato-Numata et al., 2016). NPo, number of open channels.

Tables

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    TABLE 1

     Mammalian anion channels: Classification and relation to cell volume and organic anion transport

    SpeciesChannel NameAbbreviationMolecule
    Ligand gatedGlycine receptorGlyRGlyR
    GABAA receptorGABAARGABAA
    GABAC receptorGABACRGABAC
    Voltage gatedClC-type chloride channelClC-1CLCN1
    ClC-2 (one of VAAC and VRAC)CLCN2
    ClC-K1CLCNK1
    ClC-K2CLCNK2
    cAMP activatedCystic fibrosis transmembrane conductance regulatorCFTR (one of VCAC and VSOAC)CFTR
    Ca2+ activatedCaCC (one of VCAC)TMEM16A/ANO1
    TMEM16B/ANO2
    TMEM16F/ANO6
    Volume activatedVolume-sensitive outwardly rectifying anion channel VSOR (one of VAAC, VRAC,a and VSOAC)LRRC8A+8C/8D/8E(+?c)
    Maxi-anion channelMaxi-Cl (one of VAAC, VRAC,a VSOAC, and MAC-1b)SLCO2A1(+?c)
    Acid activatedAcid-sensitive outwardly rectifying anion channel ASOR (one of VCAC)?
    • ↵a The VRAC abbreviation used in this work (for volume-regulated anion channel) is sometimes also referred to as the volume-regulatory anion channel.

    • ↵b Maxi-Cl is the major type of maxi-anion channel (MAC-1) (see the text for details).

    • ↵c The question mark represents some missing molecular component which may exist to reproduce a full set of phenotypes (see the text for details).

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    TABLE 2

     Pharmacological distinctions among VAACs and VCACs

    ChemicalClC-2VSORMaxi-ClCFTRCaCCASOR
    Cd2++−−−NS−
    Gd3+−−/+a+∼+++−−−
    DCPIB−++−−−−
    DIDS (out)−±∼++ VD+−±∼+ VD++∼+++
    NPPB± VD+++++ VD+−
    NFA−±−± VD+∼+++
    GlibenclamideNS± (VDb)−+∼++ VD+±
    PhloretinNS+−± VD−+
    CFTRinh-172+++ VD−/+∼++aNS+++−NS
    CaCCinh-A01NS−NSNS++NS
    T16Ainh-A01NS−/++aNSNS++∼+++NS
    GaTx1−NSNS+++−NS
    GaTx2+++NSNS−−NS
    Methadone+++NSNS−NSNS
    • Insensitivity and sensitivity are denoted by minus and plus signs, respectively, as follows: −, insensitive; ±, sensitive at sub-millimolar (100 ≤ IC50 < 1000 μM) concentrations; +, sensitive at deca-micromolar (10 ≤ IC50 < 100 μM) concentrations; ++, sensitive at micromolar (1 ≤ IC50 < 10 μM) concentrations; and +++, sensitive at sub-micromolar (IC50 < 1 μM) concentrations. NS, not studied; VD, voltage-dependent block.

    • ↵a Depending on cell type (see the text for details).

    • ↵b Voltage-dependent block only by the charged form.

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Pharmacological Reviews: 71 (1)
Pharmacological Reviews
Vol. 71, Issue 1
1 Jan 2019
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Review ArticleReview Article

Volume-Activated and Volume-Correlated Anion Channels

Yasunobu Okada, Toshiaki Okada, Kaori Sato-Numata, Md. Rafiqul Islam, Yuhko Ando-Akatsuka, Tomohiro Numata, Machiko Kubo, Takahiro Shimizu, Ranohon S. Kurbannazarova, Yoshinori Marunaka and Ravshan Z. Sabirov
Pharmacological Reviews January 1, 2019, 71 (1) 49-88; DOI: https://doi.org/10.1124/pr.118.015917

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Volume-Activated and Volume-Correlated Anion Channels

Yasunobu Okada, Toshiaki Okada, Kaori Sato-Numata, Md. Rafiqul Islam, Yuhko Ando-Akatsuka, Tomohiro Numata, Machiko Kubo, Takahiro Shimizu, Ranohon S. Kurbannazarova, Yoshinori Marunaka and Ravshan Z. Sabirov
Pharmacological Reviews January 1, 2019, 71 (1) 49-88; DOI: https://doi.org/10.1124/pr.118.015917
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  • Article
    • Visual Overview
    • Abstract
    • I. Introduction
    • II. Volume-Activated Anion Channels
    • III. Volume-Correlated Anion Channels
    • IV. Pharmacological Properties of and Distinctions between Volume-Activated Anion Channels and Volume-Correlated Anion Channels
    • V. Conclusions and Future Directions
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
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