Pflügers Archiv - European Journal of Physiology

, Volume 468, Issue 3, pp 371–383

Biophysics and Physiology of the Volume-Regulated Anion Channel (VRAC)/Volume-Sensitive Outwardly Rectifying Anion Channel (VSOR)

Invited Review

Abstract

The volume-regulated anion channel (VRAC), also known as the volume-sensitive outwardly rectifying (VSOR) anion channel or the volume-sensitive organic osmolyte/anion channel (VSOAC), is essential for cell volume regulation after swelling in most vertebrate cell types studied to date. In addition to its role in cell volume homeostasis, VRAC has been implicated in numerous other physiological and pathophysiological processes, including cancer, ischemic brain edema, cell motility, proliferation, angiogenesis, programmed cell death, and excitotoxic glutamate release. Although VRAC has been extensively biophysically, pharmacologically, and functionally characterized, its molecular identity was highly controversial until the recent identification of the leucine-rich repeats containing 8A (LRRC8A) protein as essential for the VRAC current in multiple cell types and a likely pore-forming subunit of VRAC. Members of this distantly pannexin-1-related protein family form heteromers, and in addition to LRRC8A, at least another LRRC8 family member is required for the formation of a functional VRAC. This review summarizes the biophysical and pharmacological properties of VRAC, highlights its main physiological functions and pathophysiological implications, and outlines the search for its molecular identity.

Keywords

Cell swelling Cell volume LRRC8A Osmotic RVD VRAC VSOR VSOAC 

References

  1. 1.
    Hoffmann EK (1978) Regulation of cell volume by selective changes in the leak permeabilities of Ehrlich ascites tumor cells. Alfred Benzon Symp XI:397–417Google Scholar
  2. 2.
    Hoffmann EK, Simonsen LO, Lambert IH (1984) Volume-induced increase of K+ and Cl permeabilities in Ehrlich ascites tumor cells. Role of internal Ca2+. J Membr Biol 78:211–222PubMedCrossRefGoogle Scholar
  3. 3.
    Hoffmann EK, Simonsen LO, Sjoholm C (1979) Membrane potential, chloride exchange, and chloride conductance in Ehrlich mouse ascites tumour cells. J Physiol 296:61–84PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Grinstein S, Clarke CA, Dupre A, Rothstein A (1982) Volume-induced increase of anion permeability in human lymphocytes. J Gen Physiol 80:801–823PubMedCrossRefGoogle Scholar
  5. 5.
    Grinstein S, Clarke CA, Rothstein A (1982) Increased anion permeability during volume regulation in human lymphocytes. Philos Trans R Soc Lond B Biol Sci 299:509–518PubMedCrossRefGoogle Scholar
  6. 6.
    Sarkadi B, Attisano L, Grinstein S, Buchwald M, Rothstein A (1984) Volume regulation of Chinese hamster ovary cells in anisoosmotic media. Biochim Biophys Acta 774:159–168PubMedCrossRefGoogle Scholar
  7. 7.
    Cahalan MD, Lewis RS (1988) Role of potassium and chloride channels in volume regulation by T lymphocytes. Soc Gen Physiol Ser 43:281–301PubMedGoogle Scholar
  8. 8.
    Hazama A, Okada Y (1988) Ca2+ sensitivity of volume-regulatory K+ and Cl channels in cultured human epithelial cells. J Physiol 402:687–702PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Nilius B, Oike M, Zahradnik I, Droogmans G (1994) Activation of a Cl current by hypotonic volume increase in human endothelial cells. J Gen Physiol 103:787–805PubMedCrossRefGoogle Scholar
  10. 10.
    Nilius B, Droogmans G (2003) Amazing chloride channels: an overview. Acta Physiol Scand 177:119–147PubMedCrossRefGoogle Scholar
  11. 11.
    Pedersen SF, Klausen TK, Nilius B (2015) The identification of a volume-regulated anion channel: an amazing Odyssey. Acta Physiol (Oxf) 213:868–881CrossRefGoogle Scholar
  12. 12.
    Stauber T (2015) The volume-regulated anion channel is formed by LRRC8 heteromers–molecular identification and roles in membrane transport and physiology. Biol Chem 396:975–990PubMedCrossRefGoogle Scholar
  13. 13.
    Clapham DE (1998) The list of potential volume-sensitive chloride currents continues to swell (and shrink). J Gen Physiol 111:623–624PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Hoffmann EK, Lambert IH, Pedersen SF (2009) Physiology of cell volume regulation in vertebrates. Physiol Rev 89:193–277PubMedCrossRefGoogle Scholar
  15. 15.
    Jentsch TJ, Stein V, Weinreich F, Zdebik AA (2002) Molecular structure and physiological function of chloride channels. Physiol Rev 82:503–568PubMedCrossRefGoogle Scholar
  16. 16.
    Nilius B, Eggermont J, Voets T, Buyse G, Manolopoulos V, Droogmans G (1997) Properties of volume-regulated anion channels in mammalian cells. Prog Biophys Mol Biol 68:69–119PubMedCrossRefGoogle Scholar
  17. 17.
    Okada Y (1997) Volume expansion-sensing outward-rectifier Cl- channel: fresh start to the molecular identity and volume sensor. Am J Physiol 273:C755–C789PubMedGoogle Scholar
  18. 18.
    Strange K (1998) Molecular identity of the outwardly rectifying, swelling-activated anion channel: time to reevaluate pICln. J Gen Physiol 111:617–622PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Valverde MA, Diaz M, Sepulveda FV, Gill DR, Hyde SC, Higgins CF (1992) Volume-regulated chloride channels associated with the human multidrug-resistance P-glycoprotein. Nature 355:830–833PubMedCrossRefGoogle Scholar
  20. 20.
    Paulmichl M, Li Y, Wickman K, Ackerman M, Peralta E, Clapham D (1992) New mammalian chloride channel identified by expression cloning. Nature 356:238–241PubMedCrossRefGoogle Scholar
  21. 21.
    Duan D, Winter C, Cowley S, Hume JR, Horowitz B (1997) Molecular identification of a volume-regulated chloride channel. Nature 390:417–421PubMedCrossRefGoogle Scholar
  22. 22.
    Nilius B, Droogmans G (2001) Ion channels and their functional role in vascular endothelium. Physiol Rev 81:1415–1459PubMedGoogle Scholar
  23. 23.
    Tominaga M, Tominaga T, Miwa A, Okada Y (1995) Volume-sensitive chloride channel activity does not depend on endogenous P-glycoprotein. J Biol Chem 270:27887–27893PubMedCrossRefGoogle Scholar
  24. 24.
    De GC, Sehrer J, Viana F, van AK, Eggermont J, Mertens L, Raeymaekers L, Droogmans G, Nilius B (1995) Volume-activated chloride currents are not correlated with P-glycoprotein expression. Biochem J 307(Pt 3):713–718Google Scholar
  25. 25.
    Arreola J, Begenisich T, Nehrke K, Nguyen HV, Park K, Richardson L, Yang B, Schutte BC, Lamb FS, Melvin JE (2002) Secretion and cell volume regulation by salivary acinar cells from mice lacking expression of the Clcn3 Cl- channel gene. J Physiol 545:207–216PubMedCentralPubMedCrossRefGoogle Scholar
  26. 26.
    Gong W, Xu H, Shimizu T, Morishima S, Tanabe S, Tachibe T, Uchida S, Sasaki S, Okada Y (2004) ClC-3-independent, PKC-dependent activity of volume-sensitive Cl channel in mouse ventricular cardiomyocytes. Cell Physiol Biochem 14:213–224PubMedCrossRefGoogle Scholar
  27. 27.
    Stobrawa SM, Breiderhoff T, Takamori S, Engel D, Schweizer M, Zdebik AA, Bosl MR, Ruether K, Jahn H, Draguhn A, Jahn R, Jentsch TJ (2001) Disruption of ClC-3, a chloride channel expressed on synaptic vesicles, leads to a loss of the hippocampus. Neuron 29:185–196PubMedCrossRefGoogle Scholar
  28. 28.
    Pu WT, Krapivinsky GB, Krapivinsky L, Clapham DE (1999) pICln inhibits snRNP biogenesis by binding core spliceosomal proteins. Mol Cell Biol 19:4113–4120PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Pu WT, Wickman K, Clapham DE (2000) ICln is essential for cellular and early embryonic viability. J Biol Chem 275:12363–12366PubMedCrossRefGoogle Scholar
  30. 30.
    Li C, Breton S, Morrison R, Cannon CL, Emma F, Sanchez-Olea R, Bear C, Strange K (1998) Recombinant pICln forms highly cation-selective channels when reconstituted into artificial and biological membranes. J Gen Physiol 112:727–736PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Garavaglia ML, Rodighiero S, Bertocchi C, Manfredi R, Furst J, Gschwentner M, Ritter M, Bazzini C, Botta G, Jakab M, Meyer G, Paulmichl M (2002) ICln channels reconstituted in heart-lipid bilayer are selective to chloride. Pflugers Arch 443:748–753PubMedCrossRefGoogle Scholar
  32. 32.
    Haynes JK, Goldstein L (1993) Volume-regulatory amino acid transport in erythrocytes of the little skate, Raja erinacea. Am J Physiol 265:R173–R179PubMedGoogle Scholar
  33. 33.
    Davis CE, Patel MK, Miller JR, John JE III, Jones LR, Tucker AL, Mounsey JP, Moorman JR (2004) Effects of phospholemman expression on swelling-activated ion currents and volume regulation in embryonic kidney cells. Neurochem Res 29:177–187PubMedCrossRefGoogle Scholar
  34. 34.
    Moorman JR, Ackerman SJ, Kowdley GC, Griffin MP, Mounsey JP, Chen Z, Cala SE, O'Brian JJ, Szabo G, Jones LR (1995) Unitary anion currents through phospholemman channel molecules. Nature 377:737–740PubMedCrossRefGoogle Scholar
  35. 35.
    Moorman JR, Jones LR (1998) Phospholemman: a cardiac taurine channel involved in regulation of cell volume. Adv Exp Med Biol 442:219–228PubMedCrossRefGoogle Scholar
  36. 36.
    Dermietzel R, Hwang TK, Buettner R et al (1994) Cloning and in situ localization of a brain-derived porin that constitutes a large-conductance anion channel in astrocytic plasma membranes. Proc Natl Acad Sci U S A 91:499–503PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Landry D, Sullivan S, Nicolaides M, Redhead C, Edelman A, Field M, al-Awqati Q, Edwards J (1993) Molecular cloning and characterization of p64, a chloride channel protein from kidney microsomes. J Biol Chem 268:14948–14955PubMedGoogle Scholar
  38. 38.
    Redhead CR, Edelman AE, Brown D, Landry DW, al-Awqati Q (1992) A ubiquitous 64-kDa protein is a component of a chloride channel of plasma and intracellular membranes. Proc Natl Acad Sci U S A 89:3716–3720PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Almaca J, Tian Y, Aldehni F, Ousingsawat J, Kongsuphol P, Rock JR, Harfe BD, Schreiber R, Kunzelmann K (2009) TMEM16 proteins produce volume-regulated chloride currents that are reduced in mice lacking TMEM16A. J Biol Chem 284:28571–28578PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Juul CA, Grubb S, Poulsen KA, Kyed T, Hashem N, Lambert IH, Larsen EH, Hoffmann EK (2014) Anoctamin 6 differs from VRAC and VSOAC but is involved in apoptosis and supports volume regulation in the presence of Ca2+. Pflugers Arch 466:1899–1910PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Shimizu T, Iehara T, Sato K, Fujii T, Sakai H, 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 Cell Physiol 304:C748–C759PubMedCrossRefGoogle Scholar
  42. 42.
    Yu K, Whitlock JM, Lee K, Ortlund EA, Cui YY, Hartzell HC (2015) Identification of a lipid scrambling domain in ANO6/TMEM16F. Elife 4:e06901PubMedGoogle Scholar
  43. 43.
    Hammer C, Wanitchakool P, Sirianant L, Papiol S, Monnheimer M, Faria D, Ousingsawat J, Schramek N, Schmitt C, Margos G, Michel A, Kraiczy P, Pawlita M, Schreiber R, Schulz TF, Fingerle V, Tumani H, Ehrenreich H, Kunzelmann K (2015) A coding variant of ANO10, affecting volume regulation of macrophages, is associated with Borrelia seropositivity. Mol Med 21:26–37PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Kunzelmann K (2015) TMEM16, LRRC8A, bestrophin: chloride channels controlled by Ca2+ and cell volume. Trends Biochem Sci 40(535–543):2015Google Scholar
  45. 45.
    Chien LT, Hartzell HC (2007) Drosophila bestrophins are dually regulated by calcium and cell volume. J Gen Physiol 130:21A–22ACrossRefGoogle Scholar
  46. 46.
    Stotz SC, Clapham DE (2012) Anion-sensitive fluorophore identifies the Drosophila swell-activated chloride channel in a genome-wide RNA interference screen. PLoS ONE 7:e46865PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Chien LT, Hartzell HC (2008) Rescue of volume-regulated anion current by bestrophin mutants with altered charge selectivity. J Gen Physiol 132:537–546PubMedCentralPubMedCrossRefGoogle Scholar
  48. 48.
    Milenkovic A, Brandl C, Milenkovic VM, Jendryke T, Sirianant L, Wanitchakool P, Zimmermann S, Reiff CM, Horling F, Schrewe H, Schreiber R, Kunzelmann K, Wetzel CH, Weber BH (2015) Bestrophin 1 is indispensable for volume regulation in human retinal pigment epithelium cells. Proc Natl Acad Sci U S A 112:E2630–E2639PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Okada Y, Sato K, Numata T (2009) Pathophysiology and puzzles of the volume-sensitive outwardly rectifying anion channel. J Physiol 587:2141–2149PubMedCentralPubMedGoogle Scholar
  50. 50.
    Ise T, Shimizu T, Lee EL, Inoue H, Kohno K, Okada Y (2005) Roles of volume-sensitive Cl- channel in cisplatin-induced apoptosis in human epidermoid cancer cells. J Membr Biol 205:139–145PubMedCrossRefGoogle Scholar
  51. 51.
    Maeno E, Ishizaki Y, Kanaseki T, Hazama A, Okada Y (2000) Normotonic cell shrinkage because of disordered volume regulation is an early prerequisite to apoptosis. Proc Natl Acad Sci U S A 97:9487–9492PubMedCentralPubMedCrossRefGoogle Scholar
  52. 52.
    Planells-Cases R, Lutter D, Guyader C, Gerhards NM, Ullrich F, Elger DA, Kucukosmanoglu A, Xu G, Voss FK, Reincke SM, Stauber T, Blomen VA, Vis DJ, Wessels LF, Brummelkamp TR, Borst P, Rottenberg S, Jentsch TJ (2015) Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs. EMBO J 34:2993–3008PubMedCentralPubMedCrossRefGoogle Scholar
  53. 53.
    Shimizu T, Numata T, Okada Y (2004) A role of reactive oxygen species in apoptotic activation of volume-sensitive Cl channel. Proc Natl Acad Sci U S A 101:6770–6773PubMedCentralPubMedCrossRefGoogle Scholar
  54. 54.
    Akita T, Fedorovich SV, 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 28:1181–1190PubMedCrossRefGoogle Scholar
  55. 55.
    Akita T, Okada Y (2011) Regulation of bradykinin-induced activation of volume-sensitive outwardly rectifying anion channels by Ca2+ nanodomains in mouse astrocytes. J Physiol 589:3909–3927PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Akita T, Okada Y (2014) Characteristics and roles of the volume-sensitive outwardly rectifying (VSOR) anion channel in the central nervous system. Neuroscience 275:211–231PubMedCrossRefGoogle Scholar
  57. 57.
    Inoue H, Okada Y (2007) Roles of volume-sensitive chloride channel in excitotoxic neuronal injury. J Neurosci 27:1445–1455PubMedCrossRefGoogle Scholar
  58. 58.
    Liu HT, Akita T, Shimizu T, Sabirov RZ, Okada Y (2009) Bradykinin-induced astrocyte-neuron signalling: glutamate release is mediated by ROS-activated volume-sensitive outwardly rectifying anion channels. J Physiol 587:2197–2209PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Voss FK, Ullrich F, Munch J, Lazarow K, Lutter D, Mah N, Andrade-Navarro MA, von Kries JP, Stauber T, Jentsch TJ (2014) Identification of LRRC8 heteromers as an essential component of the volume-regulated anion channel VRAC. Science 344:634–638PubMedCrossRefGoogle Scholar
  60. 60.
    Qiu Z, Dubin AE, Mathur J, Tu B, Reddy K, Miraglia LJ, Reinhardt J, Orth AP, Patapoutian A (2014) SWELL1, a plasma membrane protein, is an essential component of volume-regulated anion channel. Cell 157:447–458PubMedCentralPubMedCrossRefGoogle Scholar
  61. 61.
    Voets T, Nilius B, Vennekens R (2015) VRACs swallow platinum drugs. EMBO J 34:2985–2987PubMedCrossRefGoogle Scholar
  62. 62.
    Nilius B, Prenen J, Voets T, Eggermont J, Droogmans G (1998) Activation of volume-regulated chloride currents by reduction of intracellular ionic strength in bovine endothelial cells. J Physiol 506(Pt 2):353–361PubMedCentralPubMedCrossRefGoogle Scholar
  63. 63.
    Sabirov RZ, Prenen J, Tomita T, Droogmans G, Nilius B (2000) Reduction of ionic strength activates single volume-regulated anion channels (VRAC) in endothelial cells. Pflugers Arch 439:315–320PubMedCrossRefGoogle Scholar
  64. 64.
    Voets T, Droogmans G, Raskin G, Eggermont J, Nilius B (1999) Reduced intracellular ionic strength as the initial trigger for activation of endothelial volume-regulated anion channels. Proc Natl Acad Sci U S A 96:5298–5303PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Kumar L, Chou J, Yee CS, Borzutzky A, Vollmann EH, von Andrian UH, Park SY, Hollander G, Manis JP, Poliani PL, Geha RS (2014) Leucine-rich repeat containing 8A (LRRC8A) is essential for T lymphocyte development and function. J Exp Med 211:929–942PubMedCentralPubMedCrossRefGoogle Scholar
  66. 66.
    Sawada A, Takihara Y, Kim JY, Matsuda-Hashii Y, Tokimasa S, Fujisaki H, Kubota K, Endo H, Onodera T, Ohta H, Ozono K, Hara J (2003) A congenital mutation of the novel gene LRRC8 causes agammaglobulinemia in humans. J Clin Invest 112:1707–1713PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Pedersen SF, Prenen J, Droogmans G, Hoffmann EK, Nilius B (1998) Separate swelling- and Ca2+-activated anion currents in Ehrlich ascites tumor cells. J Membr Biol 163:97–110PubMedCrossRefGoogle Scholar
  68. 68.
    Strange K, Emma F, Jackson PS (1996) Cellular and molecular physiology of volume-sensitive anion channels. Am J Physiol 270:C711–C730PubMedGoogle Scholar
  69. 69.
    Okada Y, Petersen CC, Kubo M, Morishima S, Tominaga M (1994) Osmotic swelling activates intermediate-conductance Cl channels in human intestinal epithelial cells. Jpn J Physiol 44:403–409PubMedCrossRefGoogle Scholar
  70. 70.
    Jackson PS, Strange K (1995) Single-channel properties of a volume-sensitive anion conductance. Current activation occurs by abrupt switching of closed channels to an open state. J Gen Physiol 105:643–660PubMedCrossRefGoogle Scholar
  71. 71.
    Jackson PS, Strange K (1996) Single channel properties of a volume sensitive anion channel: lessons from noise analysis. Kidney Int 49:1695–1699PubMedCrossRefGoogle Scholar
  72. 72.
    Nilius B, Voets T, Eggermont J, Droogmans G (1999) VRAC: a multifunctional volume-regulated anion channel in vascular endothelium. In: Chloride channels. Oxford: Isis Medical Media LtdGoogle Scholar
  73. 73.
    Solc CK, Wine JJ (1991) Swelling-induced and depolarization-induced C1-channels in normal and cystic fibrosis epithelial cells. Am J Physiol 261:C658–C674PubMedGoogle Scholar
  74. 74.
    Worrell RT, Butt AG, Cliff WH, Frizzell RA (1989) A volume-sensitive chloride conductance in human colonic cell line T84. Am J Physiol 256:C1111–C1119PubMedGoogle Scholar
  75. 75.
    Voets T, Droogmans G, Nilius B (1997) Modulation of voltage-dependent properties of a swelling-activated Cl current. J Gen Physiol 110:313–325PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    Hagiwara N, Masuda H, Shoda M, Irisawa H (1992) Stretch-activated anion currents of rabbit cardiac myocytes. J Physiol 456:285–302PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Kubo M, Okada Y (1992) Volume-regulatory Cl channel currents in cultured human epithelial cells. J Physiol 456:351–371PubMedCentralPubMedCrossRefGoogle Scholar
  78. 78.
    Rasola A, Galietta LJ, Gruenert DC, Romeo G (1992) Ionic selectivity of volume-sensitive currents in human epithelial cells. Biochim Biophys Acta 1139:319–323PubMedCrossRefGoogle Scholar
  79. 79.
    Droogmans G, Maertens C, Prenen J, Nilius B (1999) Sulphonic acid derivatives as probes of pore properties of volume-regulated anion channels in endothelial cells. Br J Pharmacol 128:35–40PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    Droogmans G, Prenen J, Eggermont J, Voets T, Nilius B (1998) Voltage-dependent block of endothelial volume-regulated anion channels by calix[4]arenes. Am J Physiol 275:C646–C652PubMedGoogle Scholar
  81. 81.
    Ternovsky VI, Okada Y, Sabirov RZ (2004) Sizing the pore of the volume-sensitive anion channel by differential polymer partitioning. FEBS Lett 576:433–436PubMedCrossRefGoogle Scholar
  82. 82.
    Kirk K, Ellory JC, Young JD (1992) Transport of organic substrates via a volume-activated channel. J Biol Chem 267:23475–23478PubMedGoogle Scholar
  83. 83.
    Kirk K (1997) Swelling-activated organic osmolyte channels. J Membr Biol 158:1–16PubMedCrossRefGoogle Scholar
  84. 84.
    Shennan DB (2008) Swelling-induced taurine transport: relationship with chloride channels, anion-exchangers and other swelling-activated transport pathways. Cell Physiol Biochem 21:15–28PubMedCrossRefGoogle Scholar
  85. 85.
    Blum AE, Walsh BC, Dubyak GR (2010) Extracellular osmolarity modulates G protein-coupled receptor-dependent ATP release from 1321N1 astrocytoma cells. Am J Physiol Cell Physiol 298:C386–C396PubMedCentralPubMedCrossRefGoogle Scholar
  86. 86.
    Burow P, Markwardt F (2014) When S1P meets ATP. Channels (Austin) 8:385–386CrossRefGoogle Scholar
  87. 87.
    Hisadome K, Koyama T, Kimura C, Droogmans G, Ito Y, Oike M (2002) Volume-regulated anion channels serve as an auto/paracrine nucleotide release pathway in aortic endothelial cells. J Gen Physiol 119:511–520PubMedCentralPubMedCrossRefGoogle Scholar
  88. 88.
    Tsumura T, Oiki S, Ueda S, Okuma M, Okada Y (1996) Sensitivity of volume-sensitive Cl- conductance in human epithelial cells to extracellular nucleotides. Am J Physiol 271:C1872–C1878PubMedGoogle Scholar
  89. 89.
    Lee CC, Freinkman E, Sabatini DM, Ploegh HL (2014) The protein synthesis inhibitor blasticidin s enters mammalian cells via leucine-rich repeat-containing protein 8D. J Biol Chem 289:17124–17131PubMedCentralPubMedCrossRefGoogle Scholar
  90. 90.
    Helix N, Strobaek D, Dahl BH, Christophersen P (2003) Inhibition of the endogenous volume-regulated anion channel (VRAC) in HEK293 cells by acidic di-aryl-ureas. J Membr Biol 196:83–94PubMedCrossRefGoogle Scholar
  91. 91.
    Klausen TK, Bergdahl A, Hougaard C, Christophersen P, Pedersen SF, Hoffmann EK (2007) Cell cycle-dependent activity of the volume- and Ca2+-activated anion currents in Ehrlich Lettre ascites cells. J Cell Physiol 210:831–842PubMedCrossRefGoogle Scholar
  92. 92.
    Abdullaev IF, Rudkouskaya A, Schools GP, Kimelberg HK, Mongin AA (2006) Pharmacological comparison of swelling-activated excitatory amino acid release and Cl currents in cultured rat astrocytes. J Physiol 572:677–689PubMedCentralPubMedCrossRefGoogle Scholar
  93. 93.
    Decher T, Lang TJ, Nilius B, Bruggemann A, Busch TE, Steinmeyer K (2001) DCPIB is a novel selective blocker of I-Cl, I-swell and prevents swelling-induced shortening of guinea-pig atrial action potential duration. Br J Pharmacol 134:1467–1479PubMedCentralPubMedCrossRefGoogle Scholar
  94. 94.
    Harrigan TJ, Abdullaev IF, Jourd'heuil D, Mongin AA (2008) Activation of microglia with zymosan promotes excitatory amino acid release via volume-regulated anion channels: the role of NADPH oxidases. J Neurochem 106:2449–2462PubMedCentralPubMedCrossRefGoogle Scholar
  95. 95.
    Maertens C, Droogmans G, Verbesselt R, Nilius B (2002) Block of volume-regulated anion channels by selective serotonin reuptake inhibitors. Naunyn Schmiedebergs Arch Pharmacol 366:158–165PubMedCrossRefGoogle Scholar
  96. 96.
    Maertens C, Wei L, Voets T, Droogmans G, Nilius B (1999) Block by fluoxetine of volume-regulated anion channels. Br J Pharmacol 126:508–514PubMedCentralPubMedCrossRefGoogle Scholar
  97. 97.
    Maertens C, Wei L, Droogmans G, Nilius B (2000) Inhibition of volume-regulated and calcium-activated chloride channels by the antimalarial mefloquine. J Pharmacol Exp Ther 295:29–36PubMedGoogle Scholar
  98. 98.
    Maertens C, Droogmans G, Chakraborty P, Nilius B (2001) Inhibition of volume-regulated anion channels in cultured endothelial cells by the anti-oestrogens clomiphene and nafoxidine. Br J Pharmacol 132:135–142PubMedCentralPubMedCrossRefGoogle Scholar
  99. 99.
    Nilius B, Prenen J, Kamouchi M, Viana F, Voets T, Droogmans G (1997) Inhibition by mibefradil, a novel calcium channel antagonist, of Ca2+- and volume-activated Cl channels in macrovascular endothelial cells. Br J Pharmacol 121:547–555PubMedCentralPubMedCrossRefGoogle Scholar
  100. 100.
    Poletto Chaves LA, Varanda WA (2008) Volume-activated chloride channels in mice Leydig cells. Pflugers Arch 457:493–504PubMedCrossRefGoogle Scholar
  101. 101.
    Fan HT, Morishima S, Kida H, Okada Y (2001) Phloretin differentially inhibits volume-sensitive and cyclic AMP-activated, but not Ca-activated, Cl channels. Br J Pharmacol 133:1096–1106PubMedCentralPubMedCrossRefGoogle Scholar
  102. 102.
    Ye ZC, Oberheim N, Kettenmann H, Ransom BR (2009) Pharmacological “cross-inhibition” of connexin hemichannels and swelling activated anion channels. Glia 57:258–269PubMedCentralPubMedCrossRefGoogle Scholar
  103. 103.
    Motais R, Guizouarn H, Garcia-Romeu F (1991) Red cell volume regulation: the pivotal role of ionic strength in controlling swelling-dependent transport systems. Biochim Biophys Acta 1075:169–180PubMedCrossRefGoogle Scholar
  104. 104.
    Emma F, McManus M, Strange K (1997) Intracellular electrolytes regulate the volume set point of the organic osmolyte/anion channel VSOAC. Am J Physiol 272:C1766–C1775PubMedGoogle Scholar
  105. 105.
    Strange K (1994) Are all cell volume changes the same? News Physiol Sci 9:223–228Google Scholar
  106. 106.
    Doroshenko P, Neher E (1992) Volume-sensitive chloride conductance in bovine chromaffin cell membrane. J Physiol 449:197–218PubMedCentralPubMedCrossRefGoogle Scholar
  107. 107.
    Voets T, Manolopoulos V, Eggermont J, Ellory C, Droogmans G, Nilius B (1998) Regulation of a swelling-activated chloride current in bovine endothelium by protein tyrosine phosphorylation and G proteins. J Physiol 506(Pt 2):341–352PubMedCentralPubMedCrossRefGoogle Scholar
  108. 108.
    Wang Y, Roman R, Lidofsky SD, Fitz JG (1996) Autocrine signaling through ATP release represents a novel mechanism for cell volume regulation. Proc Natl Acad Sci U S A 93:12020–12025PubMedCentralPubMedCrossRefGoogle Scholar
  109. 109.
    Mongin AA, Kimelberg HK (2002) ATP potently modulates anion channel-mediated excitatory amino acid release from cultured astrocytes. Am J Physiol Cell Physiol 283:C569–C578PubMedCrossRefGoogle Scholar
  110. 110.
    Browe DM, Baumgarten CM (2004) Angiotensin II (AT1) receptors and NADPH oxidase regulate Cl current elicited by beta1 integrin stretch in rabbit ventricular myocytes. J Gen Physiol 124:273–287PubMedCentralPubMedCrossRefGoogle Scholar
  111. 111.
    Varela D, Simon F, Riveros A, Jorgensen F, Stutzin A (2004) NAD(P)H oxidase-derived H(2)O(2) signals chloride channel activation in cell volume regulation and cell proliferation. J Biol Chem 279:13301–13304PubMedCrossRefGoogle Scholar
  112. 112.
    Ando-Akatsuka Y, Shimizu T, Numata T, Okada Y (2012) Involvements of the ABC protein ABCF2 and alpha-actinin-4 in regulation of cell volume and anion channels in human epithelial cells. J Cell Physiol 227:3498–3510PubMedCrossRefGoogle Scholar
  113. 113.
    Burow P, Klapperstuck M, Markwardt F (2015) Activation of ATP secretion via volume-regulated anion channels by sphingosine-1-phosphate in RAW macrophages. Pflugers Arch 467:1215–1226PubMedCrossRefGoogle Scholar
  114. 114.
    Klausen TK, Hougaard C, Hoffmann EK, Pedersen SF (2006) Cholesterol modulates the volume-regulated anion current in Ehrlich-Lettre ascites cells via effects on Rho and F-actin. Am J Physiol Cell Physiol 291:C757–C771PubMedCrossRefGoogle Scholar
  115. 115.
    Nilius B, Voets T, Prenen J, Barth H, Aktories K, Kaibuchi K, Droogmans G, Eggermont J (1999) Role of Rho and Rho kinase in the activation of volume-regulated anion channels in bovine endothelial cells. J Physiol 516(Pt 1):67–74PubMedCentralPubMedCrossRefGoogle Scholar
  116. 116.
    Pedersen SF, Beisner KH, Hougaard C, Willumsen BM, Lambert IH, Hoffmann EK (1992) Rho family GTP binding proteins are involved in the regulatory volume decrease process in NIH3T3 mouse fibroblasts. J Physiol 541:779–796CrossRefGoogle Scholar
  117. 117.
    Tilly BC, Edixhoven MJ, Tertoolen LG, Morii N, Saitoh Y, Narumiya S, de Jonge HR (1996) Activation of the osmo-sensitive chloride conductance involves P21rho and is accompanied by a transient reorganization of the F-actin cytoskeleton. Mol Biol Cell 7:1419–1427PubMedCentralPubMedCrossRefGoogle Scholar
  118. 118.
    Feranchak AP, Roman RM, Schwiebert EM, Fitz JG (1998) Phosphatidylinositol 3-kinase contributes to cell volume regulation through effects on ATP release. J Biol Chem 273:14906–14911PubMedCrossRefGoogle Scholar
  119. 119.
    Carton I, Trouet D, Hermans D, Barth H, Aktories K, Droogmans G, Jorgensen NK, Hoffmann EK, Nilius B, Eggermont J (2002) RhoA exerts a permissive effect on volume-regulated anion channels in vascular endothelial cells. Am J Physiol Cell Physiol 283:C115–C125PubMedCrossRefGoogle Scholar
  120. 120.
    Du XL, Gao Z, Lau CP, Chiu SW, Tse HF, Baumgarten CM, Li GR (2004) Differential effects of tyrosine kinase inhibitors on volume-sensitive chloride current in human atrial myocytes: evidence for dual regulation by Src and EGFR kinases. J Gen Physiol 123:427–439PubMedCentralPubMedCrossRefGoogle Scholar
  121. 121.
    Lepple-Wienhues A, Szabo I, Laun T, Kaba NK, Gulbins E, Lang F (1998) The tyrosine kinase p56lck mediates activation of swelling-induced chloride channels in lymphocytes. J Cell Biol 141:281–286PubMedCentralPubMedCrossRefGoogle Scholar
  122. 122.
    Tilly BC, den Van BN, Tertoolen LG, Edixhoven MJ, de Jonge HR (1993) Protein tyrosine phosphorylation is involved in osmoregulation of ionic conductances. J Biol Chem 268:19919–19922PubMedGoogle Scholar
  123. 123.
    Levitan I, Christian AE, Tulenko TN, Rothblat GH (2000) Membrane cholesterol content modulates activation of volume-regulated anion current in bovine endothelial cells. J Gen Physiol 115:405–416PubMedCentralPubMedCrossRefGoogle Scholar
  124. 124.
    Romanenko VG, Rothblat GH, Levitan I (2004) Sensitivity of volume-regulated anion current to cholesterol structural analogues. J Gen Physiol 123:77–87PubMedCentralPubMedCrossRefGoogle Scholar
  125. 125.
    Nilius B, Gerke V, Prenen J, Szucs G, Heinke S, Weber K, Droogmans G (1996) Annexin II modulates volume-activated chloride currents in vascular endothelial cells. J Biol Chem 271:30631–30636PubMedCrossRefGoogle Scholar
  126. 126.
    Trouet D, Hermans D, Droogmans G, Nilius B, Eggermont J (2001) Inhibition of volume-regulated anion channels by dominant-negative caveolin-1. Biochem Biophys Res Commun 284:461–465PubMedCrossRefGoogle Scholar
  127. 127.
    Trouet D, Nilius B, Jacobs A, Remacle C, Droogmans G, Eggermont J (1999) Caveolin-1 modulates the activity of the volume-regulated chloride channel. J Physiol 520(Pt 1):113–119PubMedCentralPubMedCrossRefGoogle Scholar
  128. 128.
    Lang F, Busch GL, Ritter M, Volkl H, Waldegger S, Gulbins E, Haussinger D (1998) Functional significance of cell volume regulatory mechanisms. Physiol Rev 78:247–306PubMedGoogle Scholar
  129. 129.
    Wehner F, Olsen H, Tinel H, Kinne-Saffran E, Kinne RKH (2003) Cell volume regulation: osmolytes, osmolyte transport, and signal transduction. Rev Physiol Biochem Pharmacol 148:1–80PubMedGoogle Scholar
  130. 130.
    Forsyth SE, Hoger A, Hoger JH (1997) Molecular cloning and expression of a bovine endothelial inward rectifier potassium channel. FEBS Lett 409:277–282PubMedCrossRefGoogle Scholar
  131. 131.
    Kamouchi M, Trouet D, De GC, Droogmans G, Eggermont J, Nilius B (1997) Functional effects of expression of hslo Ca2+ activated K+ channels in cultured macrovascular endothelial cells. Cell Calcium 22:497–506PubMedCrossRefGoogle Scholar
  132. 132.
    Voets T, Droogmans G, Nilius B (1996) Membrane currents and the resting membrane potential in cultured bovine pulmonary artery endothelial cells. J Physiol 497(Pt 1):95–107PubMedCentralPubMedCrossRefGoogle Scholar
  133. 133.
    Shimizu T, Maeno E, Okada Y (2007) Prerequisite role of persistent cell shrinkage in apoptosis of human epithelial cells. Sheng Li Xue Bao 59:512–516PubMedGoogle Scholar
  134. 134.
    Okada Y, Maeno E, Shimizu T, Dezaki K, Wang J, Morishima S (2001) Receptor-mediated control of regulatory volume decrease (RVD) and apoptotic volume decrease (AVD). J Physiol-Lond 532:3–16PubMedCentralPubMedCrossRefGoogle Scholar
  135. 135.
    Okada Y, Shimizu T, Maeno E, Tanabe S, Wang X, Takahashi N (2006) Volume-sensitive chloride channels involved in apoptotic volume decrease and cell death. J Membr Biol 209:21–29PubMedCrossRefGoogle Scholar
  136. 136.
    Tanabe S, Wang X, Takahashi N, Uramoto H, Okada Y (2005) HCO3 -independent rescue from apoptosis by stilbene derivatives in rat cardiomyocytes. FEBS Lett 579:517–522PubMedCrossRefGoogle Scholar
  137. 137.
    Wang X, Takahashi N, Uramoto H, Okada Y (2005) Chloride channel inhibition prevents ROS-dependent apoptosis induced by ischemia-reperfusion in mouse cardiomyocytes. Cell Physiol Biochem 16:147–154PubMedCrossRefGoogle Scholar
  138. 138.
    Inoue H, Ohtaki H, Nakamachi T, Shioda S, Okada Y (2007) Anion channel blockers attenuate delayed neuronal cell death induced by transient forebrain ischemia. J Neurosci Res 85:1427–1435PubMedCrossRefGoogle Scholar
  139. 139.
    Maeno E, Shimizu T, Okada Y (2006) Normotonic cell shrinkage induces apoptosis under extracellular low Cl conditions in human lymphoid and epithelial cells. Acta Physiol (Oxf) 187:217–222CrossRefGoogle Scholar
  140. 140.
    Nukui M, Shimizu T, Okada Y (2006) Normotonic cell shrinkage induced by Na+ deprivation results in apoptotic cell death in human epithelial HeLa cells. J Physiol Sci 56:335–339PubMedCrossRefGoogle Scholar
  141. 141.
    Lee EL, Shimizu T, Ise T, Numata T, Kohno K, Okada Y (2007) Impaired activity of volume-sensitive Cl- channel is involved in cisplatin resistance of cancer cells. J Cell Physiol 211:513–521PubMedCrossRefGoogle Scholar
  142. 142.
    Poulsen KA, Andersen EC, Hansen CF, Klausen TK, Hougaard C, Lambert IH, Hoffmann EK (2010) Deregulation of apoptotic volume decrease and ionic movements in multidrug-resistant tumor cells: role of chloride channels. Am J Physiol Cell Physiol 298:C14–C25PubMedCrossRefGoogle Scholar
  143. 143.
    Sorensen BH, Thorsteinsdottir UA, Lambert IH (2014) Acquired cisplatin resistance in human ovarian A2780 cancer cells correlates with shift in taurine homeostasis and ability to volume regulate. Am J Physiol Cell Physiol 307:C1071–C1080PubMedCrossRefGoogle Scholar
  144. 144.
    Dezaki K, Maeno E, Sato K, Akita T, Okada Y (2012) Early-phase occurrence of K+ and Cl- efflux in addition to Ca2+ mobilization is a prerequisite to apoptosis in HeLa cells. Apoptosis 17:821–831PubMedCrossRefGoogle Scholar
  145. 145.
    Szabo I, Lepple-Wienhues A, Kaba KN, Zoratti M, Gulbins E, Lang F (1998) Tyrosine kinase-dependent activation of a chloride channel in CD95-induced apoptosis in T lymphocytes. Proc Natl Acad Sci U S A 95:6169–6174PubMedCentralPubMedCrossRefGoogle Scholar
  146. 146.
    Wang T, Birsoy K, Hughes NW, Krupczak KM, Post Y, Wei JJ, Lander ES, Sabatini DM (2015) Identification and characterization of essential genes in the human genome. Science 350:1096–1101PubMedCentralPubMedCrossRefGoogle Scholar
  147. 147.
    Banderali U, Roy G (1992) Anion channels for amino acids in MDCK cells. Am J Physiol 263:C1200–C1207PubMedGoogle Scholar
  148. 148.
    Hyzinski-Garcia MC, Rudkouskaya A, Mongin AA (2014) LRRC8A protein is indispensable for swelling-activated and ATP-induced release of excitatory amino acids in rat astrocytes. J Physiol 592:4855–4862PubMedCentralPubMedCrossRefGoogle Scholar
  149. 149.
    Jackson PS, Strange K (1993) Volume-sensitive anion channels mediate swelling-activated inositol and taurine efflux. Am J Physiol 265:C1489–C1500PubMedGoogle Scholar
  150. 150.
    Kimelberg HK, Goderie SK, Higman S, Pang S, Waniewski RA (1990) Swelling-induced release of glutamate, aspartate, and taurine from astrocyte cultures. J Neurosci 10:1583–1591PubMedGoogle Scholar
  151. 151.
    Mulligan SJ, MacVicar BA (2006) VRACs CARVe a path for novel mechanisms of communication in the CNS. Sci STKE 2006:e42CrossRefGoogle Scholar
  152. 152.
    Kimelberg HK (2005) Astrocytic swelling in cerebral ischemia as a possible cause of injury and target for therapy. Glia 50:389–397PubMedCrossRefGoogle Scholar
  153. 153.
    Kimelberg HK, MacVicar BA, Sontheimer H (2006) Anion channels in astrocytes: biophysics, pharmacology, and function. Glia 54:747–757PubMedCentralPubMedCrossRefGoogle Scholar
  154. 154.
    Mongin AA (2007) Disruption of ionic and cell volume homeostasis in cerebral ischemia: the perfect storm. Pathophysiology 14:183–193PubMedCentralPubMedCrossRefGoogle Scholar
  155. 155.
    Barros LF, Hermosilla T, Castro J (2001) Necrotic volume increase and the early physiology of necrosis. Comp Biochem Physiol A Mol Integr Physiol 130:401–409PubMedCrossRefGoogle Scholar
  156. 156.
    Olney JW (1990) Excitotoxicity: an overview. Can Dis Wkly Rep 16 Suppl 1E: 47–57Google Scholar
  157. 157.
    Hasbani MJ, Hyrc KL, Faddis BT, Romano C, Goldberg MP (1998) Distinct roles for sodium, chloride, and calcium in excitotoxic dendritic injury and recovery. Exp Neurol 154:241–258PubMedCrossRefGoogle Scholar
  158. 158.
    Doroshenko P, Sabanov V, Doroshenko N (2001) Cell cycle-related changes in regulatory volume decrease and volume-sensitive chloride conductance in mouse fibroblasts. J Cell Physiol 187:65–72PubMedCrossRefGoogle Scholar
  159. 159.
    Klausen TK, Preisler S, Pedersen SF, Hoffmann EK (2010) Monovalent ions control proliferation of Ehrlich Lettre ascites cells. Am J Physiol Cell Physiol 299:C714–C725PubMedCrossRefGoogle Scholar
  160. 160.
    Shen MR, Droogmans G, Eggermont J, Voets T, Ellory JC, Nilius B (2000) Differential expression of volume-regulated anion channels during cell cycle progression of human cervical cancer cells. J Physiol 529(Pt 2):385–394PubMedCentralPubMedCrossRefGoogle Scholar
  161. 161.
    Voets T, Szucs G, Droogmans G, Nilius B (1995) Blockers of volume-activated Cl currents inhibit endothelial cell proliferation. Pflugers Arch 431:132–134PubMedCrossRefGoogle Scholar
  162. 162.
    Chen L, Wang L, Zhu L, Nie S, Zhang J, Zhong P, Cai B, Luo H, Jacob TJ (2002) Cell cycle-dependent expression of volume-activated chloride currents in nasopharyngeal carcinoma cells. Am J Physiol Cell Physiol 283:C1313–C1323PubMedCrossRefGoogle Scholar
  163. 163.
    Nilius B (2001) Chloride channels go cell cycling. J Physiol 532:581PubMedCentralPubMedCrossRefGoogle Scholar
  164. 164.
    Voets T, Wei L, De SP, van DW, Eggermont J, Droogmans G, Nilius B (1997) Downregulation of volume-activated Cl currents during muscle differentiation. Am J Physiol 272:C667–C674PubMedGoogle Scholar
  165. 165.
    Urrego D, Tomczak AP, Zahed F, Stuhmer W, Pardo LA (2014) Potassium channels in cell cycle and cell proliferation. Philos Trans R Soc Lond B Biol Sci 369:20130094PubMedCentralPubMedCrossRefGoogle Scholar
  166. 166.
    Ginzberg MB, Kafri R, Kirschner M (2015) Cell biology. On being the right (cell) size. Science 348:1245075PubMedCrossRefGoogle Scholar
  167. 167.
    Habela CW, Sontheimer H (2007) Cytoplasmic volume condensation is an integral part of mitosis. Cell Cycle 6:1613–1620PubMedCentralPubMedCrossRefGoogle Scholar
  168. 168.
    Pendergrass WR, Angello JC, Kirschner MD, Norwood TH (1991) The relationship between the rate of entry into S phase, concentration of DNA polymerase alpha, and cell volume in human diploid fibroblast-like monokaryon cells. Exp Cell Res 192:418–425PubMedCrossRefGoogle Scholar
  169. 169.
    Rouzaire-Dubois B, Malo M, Milandri JB, Dubois JM (2004) Cell size-proliferation relationship in rat glioma cells. Glia 45:249–257PubMedCrossRefGoogle Scholar
  170. 170.
    Rouzaire-Dubois B, Milandri JB, Bostel S, Dubois JM (2000) Control of cell proliferation by cell volume alterations in rat C6 glioma cells. Pflugers Arch 440:881–888PubMedCrossRefGoogle Scholar
  171. 171.
    Mao J, Wang L, Fan A, Wang J, Xu B, Jacob TJ, Chen L (2007) Blockage of volume-activated chloride channels inhibits migration of nasopharyngeal carcinoma cells. Cell Physiol Biochem 19:249–258PubMedCrossRefGoogle Scholar
  172. 172.
    Ransom CB, O'Neal JT, Sontheimer H (2001) Volume-activated chloride currents contribute to the resting conductance and invasive migration of human glioma cells. J Neurosci 21:7674–7683PubMedGoogle Scholar
  173. 173.
    Schneider L, Klausen TK, Stock C, Mally S, Christensen ST, Pedersen SF, Hoffmann EK, Schwab A (2008) H-ras transformation sensitizes volume-activated anion channels and increases migratory activity of NIH3T3 fibroblasts. Pflugers Arch 455:1055–1062PubMedCrossRefGoogle Scholar
  174. 174.
    Soroceanu L, Manning TJ Jr, Sontheimer H (1999) Modulation of glioma cell migration and invasion using Cl and K+ ion channel blockers. J Neurosci 19:5942–5954PubMedGoogle Scholar
  175. 175.
    Schwab A, Fabian A, Hanley PJ, Stock C (2012) Role of ion channels and transporters in cell migration. Physiol Rev 92:1865–1913PubMedCrossRefGoogle Scholar
  176. 176.
    Manolopoulos VG, Liekens S, Koolwijk P, Voets T, Peters E, Droogmans G, Lelkes PI, De CE, Nilius B (2000) Inhibition of angiogenesis by blockers of volume-regulated anion channels. Gen Pharmacol 34:107–116PubMedCrossRefGoogle Scholar
  177. 177.
    Ziegelhoeffer T, Scholz D, Friedrich C, Helisch A, Wagner S, Fernandez B, Schaper W (2003) Inhibition of collateral artery growth by mibefradil: possible role of volume-regulated chloride channels. Endothelium 10:237–246PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Stine F. Pedersen
    • 1
  • Yasunobu Okada
    • 2
  • Bernd Nilius
    • 3
  1. 1.Section for Cell Biology and Physiology, Department of Biology, Faculty of ScienceUniversity of CopenhagenCopenhagenDenmark
  2. 2.SOKENDAI (The Graduate University for Advanced Studies)KanagawaJapan
  3. 3.Laboratory of Ion Channel Research, Department of Cellular and Molecular MedicineKU LeuvenLeuvenBelgium

Personalised recommendations