Accessible Requires Authentication Published by De Gruyter April 14, 2015

The volume-regulated anion channel is formed by LRRC8 heteromers – molecular identification and roles in membrane transport and physiology

Tobias Stauber
From the journal Biological Chemistry


Cellular volume regulation is fundamental for numerous physiological processes. The volume-regulated anion channel, VRAC, plays a crucial role in regulatory volume decrease. This channel, which is ubiquitously expressed in vertebrates, has been vastly characterized by electrophysiological means. It opens upon cell swelling and conducts chloride and arguably organic osmolytes. VRAC has been proposed to be critically involved in various cellular and organismal functions, including cell proliferation and migration, apoptosis, transepithelial transport, swelling-induced exocytosis and intercellular communication. It may also play a role in pathological states like cancer and ischemia. Despite many efforts, the molecular identity of VRAC had remained elusive for decades, until the recent discovery of heteromers of LRRC8A with other LRRC8 family members as an essential VRAC component. This identification marks a starting point for studies on the structure-function relation, for molecular biological investigations of its cell biology and for re-evaluating the physiological roles of VRAC. This review recapitulates the identification of LRRC8 heteromers as VRAC components, depicts the similarities between LRRC8 proteins and pannexins, and discussed whether VRAC conducts larger osmolytes. Furthermore, proposed physiological functions of VRAC and the present knowledge about the physiological significance of LRRC8 proteins are summarized and collated.

Corresponding author: Tobias Stauber, Institute of Chemistry and Biochemistry, Freie Universität Berlin, Thielallee 63, D-14195 Berlin, Germany, e-mail:


I would like to thank Thomas Jentsch, Jonas Münch, Florian Ullrich and Felizia Voss for the figures and for the teamwork during the molecular identification of VRAC. I apologize to those whose work was omitted owing to space and reference limitations. I am grateful for financial support from the German Federal Ministry of Education and Research (BMBF), e:Bio grant no. 031A314.


Abascal, F. and Zardoya, R. (2012). LRRC8 proteins share a common ancestor with pannexins, and may form hexameric channels involved in cell-cell communication. Bioessays 34, 551–560. Search in Google Scholar

Akita, T., Fedorovich, S.V., and Okada, Y. (2011). Ca2+ nanodomain-mediated component of swelling-induced volume-sensitive outwardly rectifying anion current triggered by autocrine action of ATP in mouse astrocytes. Cell. Physiol. Biochem. 28, 1181–1190. Search in Google Scholar

Akita, T. and Okada, Y. (2014). Characteristics and roles of the volume-sensitive outwardly rectifying (VSOR) anion channel in the central nervous system. Neuroscience 275C, 211–231. Search in Google Scholar

Almaca, J., Tian, Y., Aldehni, F., Ousingsawat, J., Kongsuphol, P., Rock, J.R., Harfe, B.D., Schreiber, R., and Kunzelmann, K. (2009). TMEM16 proteins produce volume-regulated chloride currents that are reduced in mice lacking TMEM16A. J. Biol. Chem. 284, 28571–28578. Search in Google Scholar

Arreola, J., Begenisch, T., Nehrke, K., Nguyen, H.V., Park, K., Richardson, L., Yang, B., Schutte, B.C., Lamb, F.S., and Melvin, J.E. (2002). Secretion and cell volume regulation by salivary acinar cells from mice lacking expression of the Clcn3 Cl- channel gene. J. Physiol. 545, 207–216. Search in Google Scholar

Banderali, U. and Roy, G. (1992). Anion channels for amino acids in MDCK cells. Am. J. Physiol. 263, C1200–1207. Search in Google Scholar

Benfenati, V., Caprini, M., Nicchia, G.P., Rossi, A., Dovizio, M., Cervetto, C., Nobile, M., and Ferroni, S. (2009). Carbenoxolone inhibits volume-regulated anion conductance in cultured rat cortical astroglia. Channels 3, 323–336. Search in Google Scholar

Best, L., Brown, P.D., Sener, A., and Malaisse, W.J. (2010). Electrical activity in pancreatic islet cells: the VRAC hypothesis. Islets 2, 59–64. Search in Google Scholar

Blum, A.E., Walsh, B.C., and Dubyak, G.R. (2010). Extracellular osmolarity modulates G protein-coupled receptor-dependent ATP release from 1321N1 astrocytoma cells. Am. J. Physiol. 298, C386–396. Search in Google Scholar

Boassa, D., Ambrosi, C., Qiu, F., Dahl, G., Gaietta, G., and Sosinsky, G. (2007). Pannexin1 channels contain a glycosylation site that targets the hexamer to the plasma membrane. J. Biol. Chem. 282, 31733–31743. Search in Google Scholar

Bortner, C.D. and Cidlowski, J.A. (1998). A necessary role for cell shrinkage in apoptosis. Biochem. Pharmacol. 56, 1549–1559. Search in Google Scholar

Bortner, C.D., and Cidlowski, J.A. (2007). Cell shrinkage and monovalent cation fluxes: role in apoptosis. Arch. Biochem. Biophys. 462, 176–188. Search in Google Scholar

Bowens, N.H., Dohare, P., Kuo, Y.H., and Mongin, A.A. (2013). DCPIB, the proposed selective blocker of volume-regulated anion channels, inhibits several glutamate transport pathways in glial cells. Mol. Pharmacol. 83, 22–32. Search in Google Scholar

Burnstock, G. (2008). Purinergic signalling and disorders of the central nervous system. Nat. Rev. Drug Discov. 7, 575–590. Search in Google Scholar

Burow, P., Klapperstück, M., and Markwardt, F. (2014). Activation of ATP secretion via volume-regulated anion channels by sphingosine-1-phosphate in RAW macrophages. Pflügers Arch., electr prepub. DOI: 10.1007/s00424-014-1561-8. Search in Google Scholar

Cahalan, M.D. and Lewis, R.S. (1988). Role of potassium and chloride channels in volume regulation by T lymphocytes. Soc. Gen. Physiol. Ser. 43, 281–301. Search in Google Scholar

Cai, S., Zhang, T., Zhang, D., Qiu, G., and Liu, Y. (2015). Volume-sensitive chloride channels are involved in cisplatin treatment of osteosarcoma. Mol. Med. Rep. 11, 2465–2470. Search in Google Scholar

Catalán, M.A., Kondo, Y., Peña-Münzenmayer, G., Jaramillo, Y., Liu, F., Choi, S., Crandall, E., Borok, Z., Flodby, P., Shull, G.E., et al. (2015). A fluid secretion pathway unmasked by acinar-specific Tmem16A gene ablation in the adult mouse salivary gland. Proc. Natl. Acad. Sci. USA 112, 2263–2268. Search in Google Scholar

Chien, L.T. and Hartzell, H.C. (2007). Drosophila bestrophin-1 chloride current is dually regulated by calcium and cell volume. J. Gen. Physiol. 130, 513–524. Search in Google Scholar

Chien, L.T. and Hartzell, H.C. (2008). Rescue of volume-regulated anion current by bestrophin mutants with altered charge selectivity. J. Gen. Physiol. 132, 537–546. Search in Google Scholar

Culliford, S.J., Borg, J.J., O’Brien, M.J., and Kozlowski, R.Z. (2004). Differential effects of pyrethroids on volume-sensitive anion and organic osmolyte pathways. Clin. Exp. Pharmacol. Physiol. 31, 134–144. Search in Google Scholar

De Greef, C., Sehrer, J., Viana, F., van Acker, K., Eggermont, J., Mertens, L., Raeymaekers, L., Droogmans, G., and Nilius, B. (1995). Volume-activated chloride currents are not correlated with P-glycoprotein expression. Biochem. J. 307, 713–718. Search in Google Scholar

Decher, N., Lang, H.J., Nilius, B., Brüggemann, A., Busch, A.E., and Steinmeyer, K. (2001). DCPIB is a novel selective blocker of I(Cl,swell) and prevents swelling-induced shortening of guinea-pig atrial action potential duration. Br. J. Pharmacol. 134, 1467–1479. Search in Google Scholar

Doroshenko, P., Sabanov, V., and Doroshenko, N. (2001). Cell cycle-related changes in regulatory volume decrease and volume-sensitive chloride conductance in mouse fibroblasts. J. Cell. Physiol. 187, 65–72. Search in Google Scholar

Duan, D., Winter, C., Cowley, S., Hume, J.R., and Horowitz, B. (1997). Molecular identification of a volume-regulated chloride channel. Nature 390, 417–421. Search in Google Scholar

Duran, C., Thompson, C.H., Xiao, Q., and Hartzell, H.C. (2010). Chloride channels: often enigmatic, rarely predictable. Annu. Rev. Physiol. 72, 95–121. Search in Google Scholar

Elliott, M.R., Chekeni, F.B., Trampont, P.C., Lazarowski, E.R., Kadl, A., Walk, S.F., Park, D., Woodson, R.I., Ostankovich, M., Sharma, P., et al. (2009). Nucleotides released by apoptotic cells act as a find-me signal to promote phagocytic clearance. Nature 461, 282–286. Search in Google Scholar

Feustel, P.J., Jin, Y., and Kimelberg, H.K. (2004). Volume-regulated anion channels are the predominant contributors to release of excitatory amino acids in the ischemic cortical penumbra. Stroke 35, 1164–1168. Search in Google Scholar

Fields, R.D. and Ni, Y. (2010). Nonsynaptic communication through ATP release from volume-activated anion channels in axons. Sci. Signal. 3, ra73. Search in Google Scholar

Fiévet, B., Gabillat, N., Borgese, F., and Motais, R. (1995). Expression of band 3 anion exchanger induces chloride current and taurine transport: structure-function analysis. EMBO J. 14, 5158–5169. Search in Google Scholar

Fisher, S.K., Cheema, T.A., Foster, D.J., and Heacock, A.M. (2008). Volume-dependent osmolyte efflux from neural tissues: regulation by G-protein-coupled receptors. J. Neurochem. 106, 1998–2014. Search in Google Scholar

Foote, C.I., Zhou, L., Zhu, X., and Nicholson, B.J. (1998). The pattern of disulfide linkages in the extracellular loop regions of connexin 32 suggests a model for the docking interface of gap junctions. J. Cell Biol. 140, 1187–1197. Search in Google Scholar

Franco, R., Panayiotidis, M.I., and de la Paz, L.D. (2008). Autocrine signaling involved in cell volume regulation: the role of released transmitters and plasma membrane receptors. J. Cell. Physiol. 216, 14–28. Search in Google Scholar

Fürst, J., Bazzini, C., Jakab, M., Meyer, G., König, M., Gschwentner, M., Ritter, M., Schmarda, A., Bottà, G., Benz, R., et al. (2000). Functional reconstitution of ICln in lipid bilayers. Pflüger’s Arch. 440, 100–115. Search in Google Scholar

Galietta, L.J., Haggie, P.M., and Verkman, A.S. (2001). Green fluorescent protein-based halide indicators with improved chloride and iodide affinities. FEBS Lett. 499, 220–224. Search in Google Scholar

Gill, D.R., Hyde, S.C., Higgins, C.F., Valverde, M.A., Mintenig, G.M., and Sepúlveda, F.V. (1992). Separation of drug transport and chloride channel functions of the human multidrug resistance P-glycoprotein. Cell 71, 23–32. Search in Google Scholar

Goldstein, L. and Brill, S.R. (1991). Volume-activated taurine efflux from skate erythrocytes: possible band 3 involvement. Am. J. Physiol. 260, R1014–1020. Search in Google Scholar

Gong, W., Xu, H., Shimizu, T., Morishima, S., Tanabe, S., Tachibe, T., Uchida, S., Sasaki, S., and Okada, Y. (2004). ClC-3-independent, PKC-dependent activity of volume-sensitive Cl channel in mouse ventricular cardiomyocytes. Cell. Physiol. Biochem. 14, 213–224. Search in Google Scholar

Grinstein, S., Clarke, C.A., Dupre, A., and Rothstein, A. (1982). Volume-induced increase of anion permeability in human lymphocytes. J. Gen. Physiol. 80, 801–823. Search in Google Scholar

Gründer, S., Thiemann, A., Pusch, M., and Jentsch, T.J. (1992). Regions involved in the opening of CIC-2 chloride channel by voltage and cell volume. Nature 360, 759–762. Search in Google Scholar

Harrigan, T.J., Abdullaev, I.F., Jourd’heuil, D., and Mongin, A.A. (2008). Activation of microglia with zymosan promotes excitatory amino acid release via volume-regulated anion channels: the role of NADPH oxidases. J. Neurochem. 106, 2449–2462. Search in Google Scholar

Hartzell, H.C., Qu, Z., Yu, K., Xiao, Q., and Chien, L.T. (2008). Molecular physiology of bestrophins: multifunctional membrane proteins linked to best disease and other retinopathies. Physiol. Rev. 88, 639–672. Search in Google Scholar

Hartzell, H.C., Yu, K., Xiao, Q., Chien, L.T., and Qu, Z. (2009). Anoctamin/TMEM16 family members are Ca2+-activated Cl- channels. J. Physiol. 587, 2127–2139. Search in Google Scholar

Hasegawa, Y., Shimizu, T., Takahashi, N., and Okada, Y. (2012). The apoptotic volume decrease is an upstream event of MAP kinase activation during staurosporine-induced apoptosis in HeLa cells. Int. J. Mol. Sci. 13, 9363–9379. Search in Google Scholar

Hayashi, T., Nozaki, Y., Nishizuka, M., Ikawa, M., Osada, S., and Imagawa, M. (2011). Factor for adipocyte differentiation 158 gene disruption prevents the body weight gain and insulin resistance induced by a high-fat diet. Biol. Pharm. Bull. 34, 1257–1263. Search in Google Scholar

Haydon, P.G. and Carmignoto, G. (2006). Astrocyte control of synaptic transmission and neurovascular coupling. Physiol. Rev. 86, 1009–1031. Search in Google Scholar

Hazama, A. and Okada, Y. (1988). Ca2+ sensitivity of volume-regulatory K+ and Cl- channels in cultured human epithelial cells. J. Physiol. 402, 687–702. Search in Google Scholar

Hernández-Carballo, C.Y., De Santiago-Castillo, J.A., Rosales-Saavedra, T., Pérez-Cornejo, P., and Arreola, J. (2010). Control of volume-sensitive chloride channel inactivation by the coupled action of intracellular chloride and extracellular protons. Pflüger’s Arch. 460, 633–644. Search in Google Scholar

Hisadome, K., Koyama, T., Kimura, C., Droogmans, G., Ito, Y., and Oike, M. (2002). Volume-regulated anion channels serve as an auto/paracrine nucleotide release pathway in aortic endothelial cells. J. Gen. Physiol. 119, 511–520. Search in Google Scholar

Hoffmann, E.K. (1978). Regulation of cell volume by selective changes in the leak permeabilities of Ehrlich ascites tumor cells. Alfred Benzon Symp. XI, 397–417. Search in Google Scholar

Hoffmann, E.K., Schettino, T., and Marshall, W.S. (2007). The role of volume-sensitive ion transport systems in regulation of epithelial transport. Comp. Biochem. Physiol. 148, 29–43. Search in Google Scholar

Hoffmann, E.K., Lambert, I.H., and Pedersen, S.F. (2009). Physiology of cell volume regulation in vertebrates. Physiol. Rev. 89, 193–277. Search in Google Scholar

Hoffmann, E.K., Holm, N.B., and Lambert, I.H. (2014). Functions of volume-sensitive and calcium-activated chloride channels. IUBMB Life 66, 257–267. Search in Google Scholar

Hofmann, A., Gerrits, B., Schmidt, A., Bock, T., Bausch-Fluck, D., Aebersold, R., and Wollscheid, B. (2010). Proteomic cell surface phenotyping of differentiating acute myeloid leukemia cells. Blood 116, e26–34. Search in Google Scholar

Hübner, C.A., Schroeder, B.C., and Ehmke, H. (2015). Regulation of vascular tone and arterial blood pressure: role of chloride transport in vascular smooth muscle. Pflüger’s Arch. 467, 605–614. Search in Google Scholar

Hyzinski-García, M.C., Rudkouskaya, A., and Mongin, A.A. (2014). LRRC8A protein is indispensable for swelling-activated and ATP-induced release of excitatory amino acids in rat astrocytes. J. Physiol. 592, 4855–4862. Search in Google Scholar

Ichikawa, M., Okamura-Oho, Y., Shimokawa, K., Kondo, S., Nakamura, S., Yokota, H., Himeno, R., Lesch, K.P., and Hayashizaki, Y. (2008). Expression analysis for inverted effects of serotonin transporter inactivation. Biochem. Biophys. Res. Commun. 368, 43–49. Search in Google Scholar

Idzko, M., Ferrari, D., and Eltzschig, H.K. (2014). Nucleotide signalling during inflammation. Nature 509, 310–317. Search in Google Scholar

Inoue, H., Ohtaki, H., Nakamachi, T., Shioda, S., and Okada, Y. (2007). Anion channel blockers attenuate delayed neuronal cell death induced by transient forebrain ischemia. J. Neurosci. Res. 85, 1427–1435. Search in Google Scholar

Jackson, P.S. and Strange, K. (1993). Volume-sensitive anion channels mediate swelling-activated inositol and taurine efflux. Am. J. Physiol. 265, C1489–1500. Search in Google Scholar

Jackson, P.S. and Strange, K. (1995). Characterization of the voltage-dependent properties of a volume-sensitive anion conductance. J. Gen. Physiol. 105, 661–676. Search in Google Scholar

Jentsch, T.J., Stein, V., Weinreich, F., and Zdebik, A.A. (2002). Molecular structure and physiological function of chloride channels. Physiol. Rev. 82, 503–568. Search in Google Scholar

Juul, C.A., Grubb, S., Poulsen, K.A., Kyed, T., Hashem, N., Lambert, I.H., Larsen, E.H., and Hoffmann, E.K. (2014). Anoctamin 6 differs from VRAC and VSOAC but is involved in apoptosis and supports volume regulation in the presence of Ca2+. Pflüger’s Arch. 466, 1899–1910. Search in Google Scholar

Kenagy, R.D., Min, S.K., Mulvihill, E., and Clowes, A.W. (2011). A link between smooth muscle cell death and extracellular matrix degradation during vascular atrophy. J. Vasc. Surg. 54, 182–191 e124. Search in Google Scholar

Kimelberg, H.K. (2005). Astrocytic swelling in cerebral ischemia as a possible cause of injury and target for therapy. Glia 50, 389–397. Search in Google Scholar

Kimelberg, H.K., Goderie, S.K., Higman, S., Pang, S., and Waniewski, R.A. (1990). Swelling-induced release of glutamate, aspartate, and taurine from astrocyte cultures. J. Neurosci. 10, 1583–1591. Search in Google Scholar

Kimelberg, H.K., Feustel, P.J., Jin, Y., Paquette, J., Boulos, A., Keller, R.W., Jr., and Tranmer, B.I. (2000). Acute treatment with tamoxifen reduces ischemic damage following middle cerebral artery occlusion. Neuroreport 11, 2675–2679. Search in Google Scholar

Kirk, K. and Kirk, J. (1993). Volume-regulatory taurine release from a human lung cancer cell line. Evidence for amino acid transport via a volume-activated chloride channel. FEBS Lett. 336, 153–158. Search in Google Scholar

Kirk, K., Ellory, J.C., and Young, J.D. (1992). Transport of organic substrates via a volume-activated channel. J. Biol. Chem. 267, 23475–23478. Search in Google Scholar

Klausen, T.K., Bergdahl, A., Hougaard, C., Christophersen, P., Pedersen, S.F., and Hoffmann, E.K. (2007). Cell cycle- dependent activity of the volume- and Ca2+-activated anion currents in Ehrlich lettre ascites cells. J. Cell. Physiol. 210, 831–842. Search in Google Scholar

Kobe, B., and Kajava, A.V. (2001). The leucine-rich repeat as a protein recognition motif. Curr. Opin. Struct. Biol. 11, 725–732. Search in Google Scholar

Kondratskyi, A., Kondratska, K., Skryma, R., and Prevarskaya, N. (2014). Ion channels in the regulation of apoptosis. Biochim. Biophys. Acta. DOI: 10.1016/j.bbamem.2014.10.030 Search in Google Scholar

Koyama, T., Oike, M., and Ito, Y. (2001). Involvement of Rho-kinase and tyrosine kinase in hypotonic stress-induced ATP release in bovine aortic endothelial cells. J. Physiol. 532, 759–769. Search in Google Scholar

Kubota, K., Kim, J.Y., Sawada, A., Tokimasa, S., Fujisaki, H., Matsuda-Hashii, Y., Ozono, K., and Hara, J. (2004). LRRC8 involved in B cell development belongs to a novel family of leucine-rich repeat proteins. FEBS Lett. 564, 147–152. Search in Google Scholar

Kumar, L., Chou, J., Yee, C.S., Borzutzky, A., Vollmann, E.H., von Andrian, U.H., Park, S.Y., Hollander, G., Manis, J.P., Poliani, P.L., et al. (2014). Leucine-rich repeat containing 8A (LRRC8A) is essential for T lymphocyte development and function. J. Exp. Med. 211, 929–942. Search in Google Scholar

Lambert, I.H. and Hoffmann, E.K. (1994). Cell swelling activates separate taurine and chloride channels in Ehrlich mouse ascites tumor cells. J. Membr. Biol. 142, 289–298. Search in Google Scholar

Lambert, I.H., Kristensen, D.M., Holm, J.B., and Mortensen, O.H. (2015). Physiological role of taurine-from organism to organelle. Acta Physiol. 213, 191–212. Search in Google Scholar

Lang, F. and Hoffmann, E.K. (2012). Role of ion transport in control of apoptotic cell death. Compr. Physiol. 2, 2037–2061. Search in Google Scholar

Lang, F., Busch, G.L., Ritter, M., Volkl, H., Waldegger, S., Gulbins, E., and Haussinger, D. (1998). Functional significance of cell volume regulatory mechanisms. Physiol. Rev. 78, 247–306. Search in Google Scholar

Lang, F., Shumilina, E., Ritter, M., Gulbins, E., Vereninov, A., and Huber, S.M. (2006). Ion channels and cell volume in regulation of cell proliferation and apoptotic cell death. Contrib. Nephrol. 152, 142–160. Search in Google Scholar

Leaney, J.L., Marsh, S.J., and Brown, D.A. (1997). A swelling-activated chloride current in rat sympathetic neurones. J. Physiol. 501, 555–564. Search in Google Scholar

Lee, E.L., Shimizu, T., Ise, T., Numata, T., Kohno, K., and Okada, Y. (2007). Impaired activity of volume-sensitive Cl- channel is involved in cisplatin resistance of cancer cells. J. Cell. Physiol. 211, 513–521. Search in Google Scholar

Lee, C.C., Carette, J.E., Brummelkamp, T.R., and Ploegh, H.L. (2013). A reporter screen in a human haploid cell line identifies CYLD as a constitutive inhibitor of NF-κB. PLoS One 8, e70339. Search in Google Scholar

Lee, C.C., Freinkman, E., Sabatini, D.M., and Ploegh, H.L. (2014). The protein synthesis inhibitor blasticidin s enters mammalian cells via leucine-rich repeat-containing protein 8D. J. Biol. Chem. 289, 17124–17131. Search in Google Scholar

Lepple-Wienhues, A., Szabo, I., Laun, T., Kaba, N.K., Gulbins, E., and Lang, F. (1998). The tyrosine kinase p56lck mediates activation of swelling-induced chloride channels in lymphocytes. J. Cell Biol. 141, 281–286. Search in Google Scholar

Li, C., Breton, S., Morrison, R., Cannon, C.L., Emma, F., Sanchez-Olea, R., Bear, C., and Strange, K. (1998). Recombinant pICln forms highly cation-selective channels when reconstituted into artificial and biological membranes. J. Gen. Physiol. 112, 727–736. Search in Google Scholar

Liu, H.T., Tashmukhamedov, B.A., Inoue, H., Okada, Y., and Sabirov, R.Z. (2006). Roles of two types of anion channels in glutamate release from mouse astrocytes under ischemic or osmotic stress. Glia 54, 343–357. Search in Google Scholar

Liu, H.T., Akita, T., Shimizu, T., Sabirov, R.Z., and Okada, Y. (2009). Bradykinin-induced astrocyte-neuron signalling: glutamate release is mediated by ROS-activated volume-sensitive outwardly rectifying anion channels. J. Physiol. 587, 2197–2209. Search in Google Scholar

Lohman, A.W. and Isakson, B.E. (2014). Differentiating connexin hemichannels and pannexin channels in cellular ATP release. FEBS Lett. 588, 1379–1388. Search in Google Scholar

Lohman, A.W., Billaud, M., and Isakson, B.E. (2012). Mechanisms of ATP release and signalling in the blood vessel wall. Cardiovasc. Res. 95, 269–280. Search in Google Scholar

Maeno, E., Ishizaki, Y., Kanaseki, T., Hazama, A., and Okada, Y. (2000). Normotonic cell shrinkage because of disordered volume regulation is an early prerequisite to apoptosis. Proc. Natl. Acad. Sci. USA 97, 9487–9492. Search in Google Scholar

Manolopoulos, V.G., Voets, T., Declercq, P.E., Droogmans, G., and Nilius, B. (1997). Swelling-activated efflux of taurine and other organic osmolytes in endothelial cells. Am. J. Physiol. 273, C214–222. Search in Google Scholar

Mao, J., Wang, L., Fan, A., Wang, J., Xu, B., Jacob, T.J., and Chen, L. (2007). Blockage of volume-activated chloride channels inhibits migration of nasopharyngeal carcinoma cells. Cell. Physiol. Biochem. 19, 249–258. Search in Google Scholar

Min, X.J., Li, H., Hou, S.C., He, W., Liu, J., Hu, B., and Wang, J. (2011). Dysfunction of volume-sensitive chloride channels contributes to cisplatin resistance in human lung adenocarcinoma cells. Exp. Biol. Med. 236, 483–491. Search in Google Scholar

Mongin, A.A. and Kimelberg, H.K. (2002). ATP potently modulates anion channel-mediated excitatory amino acid release from cultured astrocytes. Am. J. Physiol. 283, C569–578. Search in Google Scholar

Mongin, A.A. and Orlov, S.N. (2001). Mechanisms of cell volume regulation and possible nature of the cell volume sensor. Pathophysiology 8, 77–88. Search in Google Scholar

Moorman, J.R., Ackerman, S.J., Kowdley, G.C., Griffin, M.P., Mounsey, J.P., Chen, Z., Cala, S.E., O’Brian, J.J., Szabo, G., and Jones, L.R. (1995). Unitary anion currents through phospholemman channel molecules. Nature 377, 737–740. Search in Google Scholar

Nielsen, M.S., Axelsen, L.N., Sorgen, P.L., Verma, V., Delmar, M., and Holstein-Rathlou, N.H. (2012). Gap junctions. Compr. Physiol. 2, 1981–2035. Search in Google Scholar

Nilius, B., Sehrer, J., Viana, F., De Greef, C., Raeymaekers, L., Eggermont, J., and Droogmans, G. (1994). Volume-activated Cl- currents in different mammalian non-excitable cell types. Pflügers Arch. 428, 364–371. Search in Google Scholar

Nilius, B., Eggermont, J., Voets, T., Buyse, G., Manolopoulos, V., and Droogmans, G. (1997a). Properties of volume-regulated anion channels in mammalian cells. Prog. Biophys. Mol. Biol. 68, 69–119. Search in Google Scholar

Nilius, B., Prenen, J., Kamouchi, M., Viana, F., Voets, T., and Droogmans, G. (1997b). Inhibition by mibefradil, a novel calcium channel antagonist, of Ca2+- and volume-activated Cl- channels in macrovascular endothelial cells. Br. J. Pharmacol. 121, 547–555. Search in Google Scholar

Nilius, B., Prenen, J., and Droogmans, G. (1998). Modulation of volume-regulated anion channels by extra- and intracellular pH. Pflügers Arch. 436, 742–748. Search in Google Scholar

Okada, Y. (1997). Volume expansion-sensing outward-rectifier Cl- channel: fresh start to the molecular identity and volume sensor. Am. J. Physiol. 273, C755–789. Search in Google Scholar

Okada, Y., Shimizu, T., Maeno, E., Tanabe, S., Wang, X., and Takahashi, N. (2006). Volume-sensitive chloride channels involved in apoptotic volume decrease and cell death. J. Membr. Biol. 209, 21–29. Search in Google Scholar

Okada, Y., Sato, K., and Numata, T. (2009). Pathophysiology and puzzles of the volume-sensitive outwardly rectifying anion channel. J. Physiol. 587, 2141–2149. Search in Google Scholar

Orlov, S.N., Platonova, A.A., Hamet, P., and Grygorczyk, R. (2013). Cell volume and monovalent ion transporters: their role in cell death machinery triggering and progression. Am. J. Physiol. 305, C361–372. Search in Google Scholar

Paulmichl, M., Li, Y., Wickman, K., Ackerman, M., Peralta, E., and Clapham, D. (1992). New mammalian chloride channel identified by expression cloning. Nature 356, 238–241. Search in Google Scholar

Pedersen, S.F., Beisner, K.H., Hougaard, C., Willumsen, B.M., Lambert, I.H., and Hoffmann, E.K. (2002). Rho family GTP binding proteins are involved in the regulatory volume decrease process in NIH3T3 mouse fibroblasts. J. Physiol. 541, 779–796. Search in Google Scholar

Pedersen, S.F., Hoffmann, E.K., and Novak, I. (2013). Cell volume regulation in epithelial physiology and cancer. Front. Physiol. 4, 233. Search in Google Scholar

Pedersen, S.F., Klausen, T.K., and Nilius, B. (2015). The identification of a volume-regulated anion channel: an amazing Odyssey. Acta Physiol. 213, 868–881. Search in Google Scholar

Penuela, S., Gehi, R., and Laird, D.W. (2013). The biochemistry and function of pannexin channels. Biochim. Biophys. Acta 1828, 15–22. Search in Google Scholar

Piepoli, A., Palmieri, O., Maglietta, R., Panza, A., Cattaneo, E., Latiano, A., Laczko, E., Gentile, A., Carella, M., Mazzoccoli, G., et al. (2012). The expression of leucine-rich repeat gene family members in colorectal cancer. Exp. Biol. Med. 237, 1123–1128. Search in Google Scholar

Poulsen, K.A., Andersen, E.C., Hansen, C.F., Klausen, T.K., Hougaard, C., Lambert, I.H., and Hoffmann, E.K. (2010). Deregulation of apoptotic volume decrease and ionic movements in multidrug-resistant tumor cells: role of chloride channels. Am. J. Physiol. 298, C14–25. Search in Google Scholar

Pu, W.T., Krapivinsky, G.B., Krapivinsky, L., and Clapham, D.E. (1999). pICln inhibits snRNP biogenesis by binding core spliceosomal proteins. Mol. Cell. Biol. 19, 4113–4120. Search in Google Scholar

Qiu, F., Wang, J. and Dahl, G. (2012). Alanine substitution scanning of pannexin1 reveals amino acid residues mediating ATP sensitivity. Purinergic Signal. 8, 81–90. Search in Google Scholar

Qiu, Z., Dubin, A.E., Mathur, J., Tu, B., Reddy, K., Miraglia, L.J., Reinhardt, J., Orth, A.P., and Patapoutian, A. (2014). SWELL1, a plasma membrane protein, is an essential component of volume-regulated anion channel. Cell 157, 447–458. Search in Google Scholar

Rosell, A., Vilalta, A., García-Berrocoso, T., Fernández-Cadenas, I., Domingues-Montanari, S., Cuadrado, E., Delgado, P., Ribó, M., Martínez-Sáez, E., Ortega-Aznar, A., et al. (2011). Brain perihematoma genomic profile following spontaneous human intracerebral hemorrhage. PLoS One 6, e16750. Search in Google Scholar

Roy, G. (1995). Amino acid current through anion channels in cultured human glial cells. J. Membr. Biol. 147, 35–44. Search in Google Scholar

Sáez, J.C. and Leybaert, L. (2014). Hunting for connexin hemichannels. FEBS Lett. 588, 1205–1211. Search in Google Scholar

Sánchez-Olea, R., Fuller, C., Benos, D., and Pasantes-Morales, H. (1995). Volume-associated osmolyte fluxes in cell lines with or without the anion exchanger. Am. J. Physiol. 269, C1280–1286. Search in Google Scholar

Sawada, A., Takihara, Y., Kim, J.Y., Matsuda-Hashii, Y., Tokimasa, S., Fujisaki, H., Kubota, K., Endo, H., Onodera, T., Ohta, H., et al. (2003). A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans. J. Clin. Invest. 112, 1707–1713. Search in Google Scholar

Schlichter, L.C., Sakellaropoulos, G., Ballyk, B., Pennefather, P.S., and Phipps, D.J. (1996). Properties of K+ and Cl- channels and their involvement in proliferation of rat microglial cells. Glia 17, 225–236. Search in Google Scholar

Schumacher, P.A., Sakellaropoulos, G., Phipps, D.J., and Schlichter, L.C. (1995). Small-conductance chloride channels in human peripheral T lymphocytes. J. Membr. Biol. 145, 217–232. Search in Google Scholar

Schwab, A., Fabian, A., Hanley, P.J., and Stock, C. (2012). Role of ion channels and transporters in cell migration. Physiol. Rev. 92, 1865–1913. Search in Google Scholar

Shen, M.R., Droogmans, G., Eggermont, J., Voets, T., Ellory, J.C., and Nilius, B. (2000). Differential expression of volume-regulated anion channels during cell cycle progression of human cervical cancer cells. J. Physiol. 529 Pt 2, 385–394. Search in Google Scholar

Shen, M., Wang, L., Wang, B., Wang, T., Yang, G., Shen, L., Wang, T., Guo, X., Liu, Y., Xia, Y., et al. (2014). Activation of volume-sensitive outwardly rectifying chloride channel by ROS contributes to ER stress and cardiac contractile dysfunction: involvement of CHOP through Wnt. Cell Death Dis. 5, e1528. Search in Google Scholar

Shennan, D.B. (2008). Swelling-induced taurine transport: relationship with chloride channels, anion-exchangers and other swelling-activated transport pathways. Cell. Physiol. Biochem. 21, 15–28. Search in Google Scholar

Shimizu, T., Numata, T., and Okada, Y. (2004). A role of reactive oxygen species in apoptotic activation of volume-sensitive Cl- channel. Proc. Natl. Acad. Sci. USA 101, 6770–6773. Search in Google Scholar

Shimizu, T., Iehara, T., Sato, K., Fujii, T., Sakai, H., and Okada, Y. (2013). TMEM16F is a component of a Ca2+-activated Cl- channel but not a volume-sensitive outwardly rectifying Cl- channel. Am. J. Physiol. 304, C748–759. Search in Google Scholar

Shimizu, T., Ohtake, H., Fujii, T., Tabuchi, Y., and Sakai, H. (2015). Volume-sensitive outwardly rectifying Cl- channels contribute to butyrate-triggered apoptosis of murine colonic epithelial MCE301 cells. J. Physiol. Sci. 65, 151–157. Search in Google Scholar

Siebert, A.P., Ma, Z., Grevet, J.D., Demuro, A., Parker, I., and Foskett, J.K. (2013). Structural and functional similarities of calcium homeostasis modulator 1 (CALHM1) ion channel with connexins, pannexins, and innexins. J. Biol. Chem. 288, 6140–6153. Search in Google Scholar

Smits, G. and Kajava, A.V. (2004). LRRC8 extracellular domain is composed of 17 leucine-rich repeats. Mol. Immunol. 41, 561–562. Search in Google Scholar

Sørensen, B.H., Thorsteinsdottir, U.A., and Lambert, I.H. (2014). Acquired cisplatin resistance in human ovarian A2780 cancer cells correlates with shift in taurine homeostasis and ability to volume regulate. Am. J. Physiol. 307, C1071–1080. Search in Google Scholar

Soroceanu, L., Manning, T.J., Jr., and Sontheimer, H. (1999). Modulation of glioma cell migration and invasion using Cl- and K+ ion channel blockers. J. Neurosci. 19, 5942–5954. Search in Google Scholar

Stobrawa, S.M., Breiderhoff, T., Takamori, S., Engel, D., Schweizer, M., Zdebik, A.A., Bösl, M.R., Ruether, K., Jahn, H., Draguhn, A., et al. (2001). Disruption of ClC-3, a chloride channel expressed on synaptic vesicles, leads to a loss of the hippocampus. Neuron 29, 185–196. Search in Google Scholar

Stotz, S.C., and Clapham, D.E. (2012). Anion-sensitive fluorophore identifies the Drosophila swell-activated chloride channel in a genome-wide RNA interference screen. PLoS One 7, e46865. Search in Google Scholar

Strange, K. and Jackson, P.S. (1995). Swelling-activated organic osmolyte efflux: a new role for anion channels. Kidney Int. 48, 994–1003. Search in Google Scholar

Strange, K., Emma, F., and Jackson, P.S. (1996). Cellular and molecular physiology of volume-sensitive anion channels. Am. J. Physiol. 270, C711–730. Search in Google Scholar

Stutzin, A., Torres, R., Oporto, M., Pacheco, P., Eguiguren, A.L., Cid, L.P., and Sepúlveda, F.V. (1999). Separate taurine and chloride efflux pathways activated during regulatory volume decrease. Am. J. Physiol. 277, C392–402. Search in Google Scholar

Thiemann, A., Gründer, S., Pusch, M., and Jentsch, T.J. (1992). A chloride channel widely expressed in epithelial and non-epithelial cells. Nature 356, 57–60. Search in Google Scholar

Tomassen, S.F., Fekkes, D., de Jonge, H.R., and Tilly, B.C. (2004). Osmotic swelling-provoked release of organic osmolytes in human intestinal epithelial cells. Am. J. Physiol. 286, C1417–1422. Search in Google Scholar

Tominaga, M., Tominaga, T., Miwa, A., and Okada, Y. (1995). Volume-sensitive chloride channel activity does not depend on endogenous P-glycoprotein. J. Biol. Chem. 270, 27887–27893. Search in Google Scholar

Tominaga, K., Kondo, C., Kagata, T., Hishida, T., Nishizuka, M., and Imagawa, M. (2004). The novel gene fad158, having a transmembrane domain and leucine-rich repeat, stimulates adipocyte differentiation. J. Biol. Chem. 279, 34840–34848. Search in Google Scholar

Tsumura, T., Oiki, S., Ueda, S., Okuma, M., and Okada, Y. (1996). Sensitivity of volume-sensitive Cl- conductance in human epithelial cells to extracellular nucleotides. Am. J. Physiol. 271, C1872–1878. Search in Google Scholar

Vakili, A., Hosseinzadeh, S.A., and Khorasani, M.Z. (2009). Peripheral administration of carbenoxolone reduces ischemic reperfusion injury in transient model of cerebral ischemia. J. Stroke Cerebrovasc. Dis. 18, 81–85. Search in Google Scholar

Valverde, M.A., Diaz, M., Sepúlveda, F.V., Gill, D.R., Hyde, S.C., and Higgins, C.F. (1992). Volume-regulated chloride channels associated with the human multidrug- resistance P-glycoprotein. Nature 355, 830–833. Search in Google Scholar

Vandenberg, J.I., Yoshida, A., Kirk, K., and Powell, T. (1994). Swelling-activated and isoprenaline-activated chloride currents in guinea pig cardiac myocytes have distinct electrophysiology and pharmacology. J. Gen. Physiol. 104, 997–1017. Search in Google Scholar

Verdon, B., Winpenny, J.P., Whitfield, K.J., Argent, B.E., and Gray, M.A. (1995). Volume-activated chloride currents in pancreatic duct cells. J. Membr. Biol. 147, 173–183. Search in Google Scholar

Voets, T., Szucs, G., Droogmans, G., and Nilius, B. (1995). Blockers of volume-activated Cl- currents inhibit endothelial cell proliferation. Pflügers Arch. 431, 132–134. Search in Google Scholar

Voets, T., Buyse, G., Tytgat, J., Droogmans, G., Eggermont, J., and Nilius, B. (1996). The chloride current induced by expression of the protein pICln in Xenopus oocytes differs from the endogenous volume-sensitive chloride current. J. Physiol. 495, 441–447. Search in Google Scholar

Voss, F.K., Ullrich, F., Münch, J., Lazarow, K., Lutter, D., Mah, N., Andrade-Navarro, M.A., von Kries, J.P., Stauber, T., and Jentsch, T.J. (2014). Identification of LRRC8 heteromers as an essential component of the volume-regulated anion channel VRAC. Science 344, 634–638. Search in Google Scholar

Wang, J., Ambrosi, C., Qiu, F., Jackson, D.G., Sosinsky, G., and Dahl, G. (2014). The membrane protein Pannexin1 forms two open-channel conformations depending on the mode of activation. Sci. Signal. 7, ra69. Search in Google Scholar

Wehner, F. (2006). Cell volume-regulated cation channels. Contrib. Nephrol. 152, 25–53. Search in Google Scholar

Wilfinger, J., Seuter, S., Tuomainen, T.P., Virtanen, J.K., Voutilainen, S., Nurmi, T., de Mello, V.D., Uusitupa, M., and Carlberg, C. (2014). Primary vitamin D receptor target genes as biomarkers for the vitamin D3 status in the hematopoietic system. J. Nutr. Biochem. 25, 875–884. Search in Google Scholar

Wilhelm, M., Schlegl, J., Hahne, H., Moghaddas Gholami, A., Lieberenz, M., Savitski, M.M., Ziegler, E., Butzmann, L., Gessulat, S., Marx, H., et al. (2014). Mass-spectrometry-based draft of the human proteome. Nature 509, 582–587. Search in Google Scholar

Zhang, Y., Zhang, H., Feustel, P.J., and Kimelberg, H.K. (2008). DCPIB, a specific inhibitor of volume regulated anion channels (VRACs), reduces infarct size in MCAo and the release of glutamate in the ischemic cortical penumbra. Exp. Neurol. 210, 514–520. Search in Google Scholar

Received: 2015-2-15
Accepted: 2015-4-2
Published Online: 2015-4-14
Published in Print: 2015-9-1

©2015 by De Gruyter