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Cellular function and control of volume-regulated anion channels

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Abstract

Restoration of cell volume after cell swelling in mammalian cells is achieved by the loss of solutes (K+, Cl−, and organic osmolytes) and the subsequent osmotically driven efflux of water. This process is generally known as regulatory volume decrease (RVD). One pathway for the swelling induced loss of Cl− (and also organic osmolytes) during RVD is the volume-regulated anion channel (VRAC). In this review, we discuss the physiological role and cellular control of VRAC. We will first highlight evidence that VRAC is more than a volume regulator and that it participates in other fundamental cellular processes such as cell proliferation and apoptosis. The second part concentrates on the Rho/Rho kinase/myosin phosphorylation cascade and on compartmentalization in caveolae as modulators of the signal transduction cascade that controls VRAC gating in vascular endothelial cells.

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References

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

    Article  PubMed  CAS  Google Scholar 

  2. Okada, Y. (1997) Volume expansion sensing outward rectifier Cl− channel: fresh start to the molecular identity and volume sensor. Am. J. Physiol. 273, C755-C789.

    PubMed  CAS  Google Scholar 

  3. Strange, K., Emma, F. and Jackson, P. S. (1996) Cellular and molecular physiology of volumesensitive anion channels. Am. J. Physiol. 270, C711-C730.

    PubMed  CAS  Google Scholar 

  4. Grunder, 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.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  6. Strange K. (1998) Molecular identity of the outwardly rectifying, swelling-activated anion channel: time to re-evaluate pICln. J. Gen. Physiol. 111, 617–622.

    Article  PubMed  CAS  Google Scholar 

  7. Clapham, D. E. (1998) The list of potential volume-sensitive chloride currents continues to swell (and shrink). J. Gen. Physiol. 111, 623–624.

    Article  PubMed  CAS  Google Scholar 

  8. Clapham, D. (2001) How to lose your hippocampus by working on chloride channels. Neuron 29, 1–3.

    Article  PubMed  CAS  Google Scholar 

  9. Okada, Y., Oiki, S., Hazama, A. and Morishima, S. (1998) Criteria for the molecular identification of the volume-sensitive outwardly rectifying Cl∟ channel. J. Gen. Physiol. 112, 365–367.

    Article  PubMed  CAS  Google Scholar 

  10. Jackson, P. S., Morrison, R. and Strange, K. (1994) The volume-sensitive organic osmolyte-anion channel VSOAC is regulated by nonhydrolytic ATP binding. Am. J. Physiol. 267, C1203-C1209.

    PubMed  CAS  Google Scholar 

  11. Duan, D. and Hume, J. R. (2000) NO and the regulation of VSOACs. J. Physiol. (Lond.) 528, 2.

    Article  CAS  Google Scholar 

  12. Chou, C. Y., Shen, M. R. and Wu, S. N. (1995) Volume-sensitive chloride channels associated with human cervical carcinogenesis. Cancer Res. 55, 6077–6083.

    PubMed  CAS  Google Scholar 

  13. 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.

    Article  PubMed  CAS  Google Scholar 

  14. Duan, D., Cowley, S., Horowitz, B. and Hume, J. R. (1999) A serine residue in CIC-3 links phosphorylation-dephosphorylation to chloride channel regulation by cell volume. J. Gen. Physiol. 113, 57–70.

    Article  PubMed  CAS  Google Scholar 

  15. Duan, D., Zhong, J., Hermoso, M., Satterwhite, C. M., Rossow, C. F., Hatton, W. J., et al. (2001) Functional inhibition of native volume-sensitive outwardly rectifying anion channels in muscle cells and Xenopus oocytes by anti-CIC-3 antibody. J. Physiol. (Lond.) 531, 437–444.

    Article  CAS  Google Scholar 

  16. Li, X. H., Shimada, K., Showalter, L. A. and Weinman, S. A. (2000) Biophysical properties of CIC-3 differentiate it from swelling-activated chloride channels in Chinese hamster ovary-K1 cells. J. Biol. Chem. 275, 35,994–35,998.

    CAS  Google Scholar 

  17. Weylandt, K.-H., Valverde, M. A., Nobles, M., Raguz, S., Amey, J. S., Diaz, M., et al. (2001) Human CIC-3 is not the swelling-activated chloride channel involved in cell volume regulation. J. Biol. Chem. 276, 17,461–17,467.

    Article  CAS  Google Scholar 

  18. Friedrich, T., Breiderhoff, T. and Jentsch, T. J. (1999) Mutational analysis demonstrates that CIC-4 and CIC-5 directly mediate plasma membrane currents. J. Biol. Chem. 274, 896–902.

    Article  PubMed  CAS  Google Scholar 

  19. Stobrawa, S. M., Breiderhoff, T., Takamori, S., Engel, D., Schweizer, M., Zdebik, et al. (2001) Disruption of CIC-3, a chloride channel expressed on synaptic vesicles, leads to a loss of the hippocampus. Neuron 29, 185–196.

    Article  PubMed  CAS  Google Scholar 

  20. Bond, T. D., Ambikapathy, S., Mohammad, S. and Valverde M. A. (1998) Osmosensitive Cl− currents and their relevance to regulatory volume decrease in human intestinal T84 cells: outwardly vs. inwardly rectifying currents. J. Physiol. (Lond.) 511, 45–54.

    Article  CAS  Google Scholar 

  21. Nilius, B., Sehrer, J., Desmet, P., Vandriessche, W. and Droogmans, G. (1995) Volume regulation in a toad epithelial cell line: role of coactivation of K+and Cl-chennels. J. Physiol. (Lond.) 487, 367–378.

    CAS  Google Scholar 

  22. Davies, P. F. (1995) Flow-mediated endothelial mechanotransduction. Physiol. Rev. 75, 519–560.

    PubMed  CAS  Google Scholar 

  23. Nakao, M., Ono, K., Fujisawa, S. and Iijima, T. (1999) Mechanical stress-induced Ca2+ entry and Cl− current in cultured human aortic endothelial cells. Am. J. Physiol. 276, C238–249.

    PubMed  CAS  Google Scholar 

  24. Barakat, A. I., Leaver, E. V., Pappone, P. A., and Davies, P. F. (1999) A flow-activated chlorideselective membrane current in vascular endothelial cells. Circ. Res. 85, 820–828.

    PubMed  CAS  Google Scholar 

  25. Nilius, B., Viana, F. and Droogmans, G. (1997) Ion channels in vascular endothelium. Annu. Rev. Physiol. 59, 145–170.

    Article  PubMed  CAS  Google Scholar 

  26. Voets, T., Droogmans, G., and Nilius, B. (1996) Membrane currents and the resting membrane potential in cultured bovine pulmonary artery endothelial cells. J. Physiol. (Lond.) 497, 95–107.

    CAS  Google Scholar 

  27. Doughty, J. M., Boyle, J. P. and Langton, P. D. (2001) Blockade of chloride channels reveals relaxations of rat small mesenteric arteries to raised potassium. Br. J. Pharmacol. 132, 293–301.

    Article  PubMed  CAS  Google Scholar 

  28. Nelson, M., Conway, M., Knot, H. and Brayden, J. (1997) Chloride channel blockers inhibit myogenic tone in rat cerebral arteries. J. Physiol. (Lond.) 502, 259–264.

    Article  CAS  Google Scholar 

  29. Nelson, M. T. (1998) Bayliss, myogenic tone and volume-regulated chloride channels in arterial smooth muscle. J. Physiol. (Lond.) 507, 629.

    Article  CAS  Google Scholar 

  30. Maertens, C., Droogmans, G., Chakraborty, P. and Nilius, B. (2001) Inhibition of volume-regulated anion channels in cultured endothelial cells by the anti-oestrogens clomiphene and nafoxidine. Br. J. Pharmacol. 132, 135–142.

    Article  PubMed  CAS  Google Scholar 

  31. Voets, T., Szücs, G., Droogmans, G. and Nilius, B. (1995) blockers of volume-activated Cl-currents inhibit endothelial cell proliferation. Pflügers Arch. Eur. J. Physiol. 431, 132–134.

    Article  CAS  Google Scholar 

  32. Rouzaire-Dubois, B. and Dubois, J. M. (1998) K+channel block-induced mammalian neuroblastoma cell swelling: a possible mechanism to influence proliferation. J. Physiol. (Lond.) 510, 93–102.

    Article  CAS  Google Scholar 

  33. Shen, M., 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. (Lond.) 529, 385–394.

    Article  CAS  Google Scholar 

  34. Wondergem, R., Gong, W., Monen, S. H., Dooley, S. N., Gonce, J. L., Conner, T. D., et al. (2001) Blocking swelling-activated chloride current inhibits mouse liver cell proliferation. J. Physiol. (Lond.) 532, 661–672.

    Article  CAS  Google Scholar 

  35. 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.

    Article  PubMed  CAS  Google Scholar 

  36. Manolopoulos, V. G., Liekens, S., Koolwijk, P., Voets, T., Peters, E., Droogmans, G., et al. (2000) Inhibition of angiogenesis by blockers of volume-regulated anion channels. Gen. Pharmacol. 34, 107–116.

    Article  PubMed  CAS  Google Scholar 

  37. Lang, F., Lepple Wienhues, A., Paulmichl, M., Szabo, I., Siemen, D. and Gulbins, E. (1998) Ion channels, cell volume, and apoptotic cell death. Cell. Physiol. Biochem. 8, 285–292.

    Article  PubMed  CAS  Google Scholar 

  38. Okada, Y., Maeno, E., Shimizu, T., Dezaki, K., Wang, J. and Morishima, S. (2001) Receptor-mediated control of regulatory volume decrease (RVD) and apoptotic volume decrease (AVD). J. Physiol. (Lond.) 532, 3–16.

    Article  CAS  Google Scholar 

  39. Yu, S. P. and Choi, D. W. (2000) Ions, cell volume, and apoptosis. Proc. Natl. Acad. Sci. USA 97, 9360–9362.

    Article  PubMed  CAS  Google Scholar 

  40. Szabo, I., LeppleWienhues, A., Kaba, K. N., Zoratti, M., Gulbins, E. and Lang, F. (1998) Tyrosine kinase-dependent activation of a chloride channel in CD95-induced apoptosis in T lymphocytes. Proc. Natl. Acad. Sci. USA 95, 6169–6174.

    Article  PubMed  CAS  Google Scholar 

  41. 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.

    Article  PubMed  CAS  Google Scholar 

  42. Souktani, R., Berdeaux, A., Ghaleh, B., Giudicelli, J. F., Guize, L., Le Heuzey, et al. (2000) Induction of apoptosis using sphingolipids activates a chloride current in Xenopus laevis oocytes. Am. J. Physiol. 279, C158-C165.

    CAS  Google Scholar 

  43. Hughes, F. M., Jr., Bortner, C. D., Purdy, G. D. and Cidlowski, J. A. (1997) Intracellular K+ suppresses the activation of apoptosis in lymphocytes. J. Biol. Chem. 272, 30,567–30,576.

    CAS  Google Scholar 

  44. Voets, T., Manolopoulos, V., Eggermont, J., Ellory, C., Droogmans, G. and Nilius, B. (1998) Regulation of a swelling-activated chloride current in bovine endothelium by protein tyrosine phosphorylation and G proteins. J. Physiol. (Lond.) 506, 341–352.

    Article  CAS  Google Scholar 

  45. Bond, T., Basavappa, S., Christensen, M. and Strange, K. (1999) ATP dependence of the I-C1,I-swell channel varies with rate of cell swelling— evidence for two modes of channel activation. J. Gen. Physiol. 113, 441–456.

    Article  PubMed  CAS  Google Scholar 

  46. Nilius, B., Oike, M., Zahradnik, I. and Droogmans, G. (1994) Activation of a C1-current by hypotonic volume increase in human endothelial cells. J. Gen. Physiol. 103, 787–805.

    Article  PubMed  CAS  Google Scholar 

  47. Lewis, R. S., Ross, P. E., and Cahalan, M. D. (1993) Chloride channels activated by osmotic stress in T lymphocytes. J. Gen. Physiol. 101, 801–826.

    Article  PubMed  CAS  Google Scholar 

  48. Doroshenko, P. and Neher, E. (1992) Volume-sensitive chloride conductance in bovine chromaffin cell membrane. J. Physiol. (Lond.) 449, 197–218.

    CAS  Google Scholar 

  49. Voets, T., Droogmans, G., Raskin, G., Eggermont, J. and Nilius, B. (1999) Reduced intracellular ionic strength as the initial trigger for activation of endothelial volume-regulated anion channels. Proc. Natl. Acad. Sci. USA 96, 5298–5303.

    Article  PubMed  CAS  Google Scholar 

  50. Nilius, B., Prenen, J., Voets, T., Eggermont, J. and Droogmans, G. (1998) Activation of volume-regulated chloride currents by reduction of intracellular ionic strength in bovine endothelial cells. J. Physiol. (Lond.) 506, 353–361.

    Article  CAS  Google Scholar 

  51. Sabirov, R. Z., Prenen, J., Tomita, T., Droogmans, G. and Nilius, B. (2000) Reduction of ionic strength activates single volume-regulated anion channels (VRAC) in endothelial cells. Pflügers Arch. Eur. J. Physiol. 439, 315–320.

    Article  CAS  Google Scholar 

  52. Jung, K., Veen, M. and Altendorf, K. (2000) K+ and ionic strength directly influence the autophosphorylation activity of the putative turgor sensor KdpD of Escherichia coli. J. Biol. Chem. 275, 40,142–40,147.

    CAS  Google Scholar 

  53. Sorota, S. (1995) Tyrosine protein kinase inhibitors prevent activation of cardiac swelling-induced chloride current. Pflügers Arch. Eur. J. Physiol. 431, 178–185.

    Article  CAS  Google Scholar 

  54. Lepple-Wienhues, A., Szabo, I., Laun, T., Kaba, N. K., Gulbins, E. and Lang, F. (1998) The tyrosine kinase p56(lck) mediates activation of swelling-induced chloride channels in lymphocytes. J. Cell Biol. 141, 281–286.

    Article  PubMed  CAS  Google Scholar 

  55. Tilly, B. C., van den Berghe, N., Tertoolen, L. G., Edixhoven,M. J. and de Jonge, H. R. (1993) Protein tyrosine phosphorylation is involved in osmoregulation of ionic conductances. J. Biol. Chem. 268, 19,919–19,922.

    CAS  Google Scholar 

  56. Du, X. Y. and Sorota, S. (1999) Protein kinase C stimulates swelling-induced chloride current in canine atrial cells. Pflugers Arch Eur. J. Physiol. 437, 227–234.

    Article  CAS  Google Scholar 

  57. Duan, D., Fermini, B. and Nattel, S. (1995) Alpha-adrenergic control of volume-regulated Cl-currents in rabbit atrial myocytes—characterization of a novel ionic regulatory mechanism. Circ. Res. 77, 379–393.

    PubMed  CAS  Google Scholar 

  58. Chou, C. Y., Shen, M. R., Hsu, K. S., Huang, H. Y. and Lin, H. C. (1998) Involvement of PKC-alpha in regulatory volume decrease responses and activation of volume-sensitive chloride channels in human cervical cancer HT-3 cells. J. Physiol. (Lond.) 512, 435–448.

    Article  CAS  Google Scholar 

  59. Trouet, D., Carton, I., Hermans, D., Droogmans G., Nilius, B. and Eggermont, J. (2001) The inhibition of volume-regulated anion channels by cSrc tyrosine kinase targeted to caveolae is mediated by the Src homology domains. Am. J. Physiol. 281, C248-C256.

    CAS  Google Scholar 

  60. Somlyo, A. P. and Somlyo, A. V. (2000) Signal transduction by G-proteins, Rho-kinase and protein phosphatase to smooth muscle and non-muscle myosin II. J. Physiol. (Lond.) 522, 177–185.

    Article  CAS  Google Scholar 

  61. Bishop, A. L. and Hall, A. (2000) Rho GTPases and their effector proteins. Biochem. J. 348, 241–255.

    Article  PubMed  CAS  Google Scholar 

  62. Mackay, D. J. G. and Hall, A. (1998) Rho GTPases. J. Biol. Chem. 273, 20,685–20,688.

    CAS  Google Scholar 

  63. Essler, M., Amano, M., Kruse, H. J., Kaibuchi, K., Weber, P. C. and Aepfelbacher, M. (1998) Thrombin inactivates myosin light chain phosphatase via rho and its target rho kinase in human endothelial cells. J. Biol. Chem. 273, 21,867–21,874.

    Article  CAS  Google Scholar 

  64. van Nieuw Amerongen, G. P., van Delft, S., Vermeer, M. A., Collard, J. G. and van Hinsbergh, V. W. (2000) Activation of RhoA by thrombin in endothelial hyperpermeability: role of Rho kinase and protein tyrosine kinases. Circ. Res. 87, 335–340.

    PubMed  Google Scholar 

  65. Gohla, A., Harhammer, R. and Schultz, G. (1998) The G-protein G13 but not G12 mediates signaling from lysophosphatidic acid receptor via epidermal growth factor receptor to Rho. J. Biol. Chem. 273, 4653–4659.

    Article  PubMed  CAS  Google Scholar 

  66. Watanabe, N., Kato, T., Fujita, A., Ishizaki, T. and Narumiya, S. (1999) Cooperation between mDial and ROCK in Rho-induced actin reorganisation. Nature Cell Biol. 1, 136–143.

    Article  PubMed  CAS  Google Scholar 

  67. Nilius, B., Voets, T., Prenen, J., Barth, H., Aktories, K., Kaibuchi, K., et al. (1999) Role of Rho and Rho kinase in the activation of volume-regulated anion channels in bovine endothelial cells. J. Physiol. (Lond.) 516, 67–74.

    Article  CAS  Google Scholar 

  68. Nilius, B., Prenen, J., Walsh, M. P., Carton, I., Bollen, M., Droogmans, G., et al. (2000) Myosin light chain phosphorylation-dependent modulation of volume-regulated anion channels in macrovascular endothelium. FEBS Lett. 466, 346–350.

    Article  PubMed  CAS  Google Scholar 

  69. Manolopoulos, G. V., Prenen, J., Droogmans, G. and Nilius, B. (1997) Thrombin potentiates volume activated chloride currents in pulmonary artery endothelial cells. Pflügers Arch. Eur. J. Physiol. 433, 845–847.

    Article  CAS  Google Scholar 

  70. Kaibuchi, K., Kuroda, S. and Amano, M. (1999) Regulation of the cytoskeleton and cell adhesion by the Rho family GTPases in mammalian cells. Annu. Rev. Biochem. 68, 459–486.

    Article  PubMed  CAS  Google Scholar 

  71. Eggermont, J., Carton, I., Trouet, D., Hermans, D., Droogmans, G. and Nilius, B. (2001) The RhoA signaling pathway exerts a permissive, not a causative effect on the activation of the volume-regulated anion channel (VRAC) in macrovascular endothelial cells. FASEB J. 15, A845.

    Google Scholar 

  72. Janmey, P. A. (1998) The cytoskeleton and cell signaling: component localization and mechanical coupling. Physiol. Rev. 78, 763–781.

    PubMed  CAS  Google Scholar 

  73. 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. (Lond.) 532, 759–769.

    Article  CAS  Google Scholar 

  74. Trouet, D., Nilius, B., Jacobs, A., Remacle, C., Droogmans, G. and Eggermont, J. (1999) Caveolin-1 modulates the activity of the volume-regulated chloride channel. J. Physiol. (Lond.) 520, 113–119.

    Article  CAS  Google Scholar 

  75. Anderson (1993) Potocytosis of small molecules and ions by caveolae. Trends Cell Biol. 3, 69–72.

    Article  PubMed  CAS  Google Scholar 

  76. Okamoto, T., Schlegel, A., Scherer, P. E. and Lisanti, M. P. (1998) Caveolins, a family of scaffolding proteins for organizing “preassembled signaling complexes” at the plasma membrane. J. Biol. Chem. 273, 5419–5422.

    Article  PubMed  CAS  Google Scholar 

  77. Trouet, D., Hermans, D., Droogmans, G., Nilius, B. and Eggermont, J. (2001) Inhibition of volume-regulated anion channels by dominant-negative caveolin-1. Biochem. Biophys. Res. Commun. 284, 461–465.

    Article  PubMed  CAS  Google Scholar 

  78. Smart, E. J., Graf, G. A., McNiven, M. A., Sessa, W. C., Engelman, J. A., Scherer, et al. (1999) Caveolins, liquid-ordered domains, and signal transduction. Mol. Cell. Biol. 19, 7289–7304.

    PubMed  CAS  Google Scholar 

  79. Scheiffele, P., Verkade, P., Fra, A. M., Virta, H., Simons, K. and Ikonen, E. (1998) Caveolin-1 and-2 in the exocytic pathway of MDCK cells. J. Cell Biol. 140, 795–806.

    Article  PubMed  CAS  Google Scholar 

  80. Rizzo, V., Sung, A., Oh, P. and Schnitzer, J. E. (1998) Rapid mechanotransduction in situ at the luminal cell surface of vascular endothelium and its caveolae. J. Biol. Chem. 273, 26,323–26,329.

    CAS  Google Scholar 

  81. Doroshenko, P. (1991) Second messengers mediating activation of chloride current by intracellular GTP gamma S in bovine chromaffin cells. J. Physiol. (Lond.) 436, 725–738.

    CAS  Google Scholar 

  82. Cannon, C. L., Basavappa, S. and Strange, K. (1998) Intracellular ionic strength regulates the volume sensitivity of a swelling-activated anion channel. Am. J. Physiol. 275, C416-C422.

    PubMed  CAS  Google Scholar 

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  1. Laboratory of Physiology, Catholic University of Leuven, Campus Gasthuisberg, B-3000, Leuven, Belgium

    Jan Eggermont, Dominique Trouet, Iris Carton & Bernd Nilius

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  1. Jan Eggermont
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  4. Bernd Nilius
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Correspondence to Jan Eggermont.

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Eggermont, J., Trouet, D., Carton, I. et al. Cellular function and control of volume-regulated anion channels. Cell Biochem Biophys 35, 263–274 (2001). https://doi.org/10.1385/CBB:35:3:263

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