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Calcium-activated chloride channels in the corpus cavernosum: recent developments and future of a key cellular component of the erectile process

International Journal of Impotence Research volume 24, pages 211–216 (2012)Cite this article

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Abstract

Calcium-activated chloride channels (CaCCs) are one of five families of chloride channels, ubiquitously expressed, and essential for a host of biological actions. CaCCs have key roles in processes as diverse as olfactory transduction and epithelial secretion, and also CaCCs are essential in smooth muscle contraction. The corpus cavernosum is a vascular smooth muscle that must relax to facilitate erections. Parasympathetic activation produces relaxation of the corpus cavernosum through a nitric oxide-dependent pathway, and sympathetic stimulation in both preventing and terminating erections by contracting the corpus cavernosum. Both these pathways affect activity of CaCCs. The past 5 years produced many successes in CaCC research. One key area of success was the identification of the elusive ‘molecular candidate’ of CaCCs, as the TMEM16A protein (dubbed anoctamin-1) and potentially other members of the anoctamin family of transmembrane proteins. However, enthusiasm has been somewhat tempered because of evidence that this family of proteins may not be responsible for calcium-activated chloride currents in certain epithelial tissues. Several studies identified specific inhibitors of CaCCs as well as specific inhibitors for anoctamin-1. Despite the number of recent achievements in this field there are many details that still need to be elucidated. Of particular value would be more details on the identity of the CaCCs in corpus cavernosum smooth muscle, using new inhibitors to gain insight into the signalling pathway, and the evaluation of whether inhibition of CaCCs provides any specific benefit in different models of ED.

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References

  1. Accardi A, Miller C . Secondary active transport mediated by a prokaryotic homologue of ClC Cl- channels. Nature 2004; 427: 803–807.

    Article  CAS  Google Scholar 

  2. Duran C, Thompson CH, Xiao Q, Hartzell HC . Chloride channels: often enigmatic, rarely predictable. Annu Rev Physiol 2010; 72: 95–121.

    Article  CAS  Google Scholar 

  3. Verkman AS, Galietta LJ . Chloride channels as drug targets. Nat Rev Drug Discov 2009; 8: 153–171.

    Article  CAS  Google Scholar 

  4. Coombs JS, Eccles JC, Fatt P . The specific ionic conductances and the ionic movements across the motoneuronal membrane that produce the inhibitory post-synaptic potential. J Physiol 1955; 130: 326–373.

    Article  CAS  Google Scholar 

  5. Krnjeviæ K, Schwartz S . The action of ã-Aminobutyric acid on cortical neurones. Exp Brain Res 1967; 3: 320–336.

    Article  Google Scholar 

  6. Werman R, Davidoff RA, Aprison MH . Inhibitory of glycine on spinal neurons in the cat. J Neurophysiol 1968; 31: 81–95.

    Article  CAS  Google Scholar 

  7. Kerem B, Rommens JM, Buchanan JA, Markiewicz D, Cox TK, Chakravarti A et al. Identification of the cystic fibrosis gene: genetic analysis. Science 1989; 245: 1073–1080.

    Article  CAS  Google Scholar 

  8. Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science 1989; 245: 1066–1073.

    Article  CAS  Google Scholar 

  9. Rommens J, Iannuzzi M, Kerem B, Drumm M, Melmer G, Dean M et al. Identification of the cystic fibrosis gene: chromosome walking and jumping. Science 1989; 245: 1059–1065.

    Article  CAS  Google Scholar 

  10. Jentsch TJ, Stein V, Weinreich F, Zdebik AA . Molecular structure and physiological function of chloride channels. Physiol Rev 2002; 82: 503–568.

    Article  CAS  Google Scholar 

  11. Mindell JA, Maduke M . ClC chloride channels. Genome Biol 2001; 2: 3001–3003.

    Article  Google Scholar 

  12. Jentsch TJ, Steinmeyer K, Schwarz G . Primary structure of Torpedo marmorata chloride channel isolated by expression cloning in Xenopus oocytes. Nature 1990; 348: 510–514.

    Article  CAS  Google Scholar 

  13. Jentsch TJ, Friedrich T, Schriever A, Yamada H . The CLC chloride channel family. Eur J Physiol 1999; 437: 783–795.

    Article  CAS  Google Scholar 

  14. Jackson PS, Strange K . Volume-sensitive anion channels mediate swelling-activated inositol and taurine efflux. Am J Physiol Cell Physiol 1993; 265: C1489–C1500.

    Article  CAS  Google Scholar 

  15. Duan D, Winter C, Cowley S, Hume JR, Horowitz B . Molecular identification of a volume-regulated chloride channel. Nature 1997; 390: 417–421.

    Article  CAS  Google Scholar 

  16. Hermoso M, Satterwhite CM, Andrade YN, Hidalgo J, Wilson SM, Horowitz B et al. ClC-3 is a fundamental molecular component of volume-sensitive outwardly rectifying Cl channels and volume regulation in HeLa cells and Xenopus laevis oocytes. J Biol Chem 2002; 277: 40066–40074.

    Article  CAS  Google Scholar 

  17. Weylandt K, Valverde MA, Nobles M, Raguz S, Amey JS, Diaz M et al. Human ClC-3 is not the swelling-activated chloride channel involved in cell volume regulation. J Biol Chem 2001; 276: 17461–17467.

    Article  CAS  Google Scholar 

  18. Barish ME . A transient calcium-dependent chloride current in the immature Xenopus oocyte. J Physiol 1983; 342: 309–325.

    Article  CAS  Google Scholar 

  19. Miledi R . A calcium-dependent transient outward current in Xenopus laevis oocytes. Proc R Soc Lond B Biol Sci 1982; 215: 491–497.

    Article  CAS  Google Scholar 

  20. Hartzell C, Putzier I, Arreola J . Calcium-activated chloride channels. Annu Rev Physiol 2005; 67: 719–758.

    Article  CAS  Google Scholar 

  21. Byrne NG, Large WA . Action of noradrenaline on single smooth muscle cells freshly dispersed from the rat anococcygeus muscle. J Physiol 1987; 389: 513–525.

    Article  CAS  Google Scholar 

  22. Byrne NG, Large WA . Membrane mechanism associated with muscarinic receptor activation in single cells freshly dispersed from the rat anococcygeus muscle. Br J Pharmacol 1987; 92: 371–379.

    Article  CAS  Google Scholar 

  23. Large WA, Wang Q . Characteristics and physiological role of the Ca(2+)-activated Cl- conductance in smooth muscle. Am J Physiol 1996; 271: C435–C454.

    Article  CAS  Google Scholar 

  24. Karkanis T, DeYoung L, Brock GB, Sims SM . Ca2+−activated Cl− channels in corpus cavernosum smooth muscle: a novel mechanism for control of penile erection. J Appl Physiol 2003; 94: 301–313.

    Article  CAS  Google Scholar 

  25. Lau LC, Adaikan PG . Role of chloride channels in the regulation of corpus cavernosum tone: a potential therapeutic target for erectile dysfunction. J Sex Med 2008; 5: 813–821.

    Article  Google Scholar 

  26. Kuo Y, Chung S, Liu S, Chang H, Yu H, Hsieh J . The role of chloride channels in rat corpus cavernosum: in vivo study. J Sex Med 2009; 6: 708–716.

    Article  CAS  Google Scholar 

  27. Andersson K . Pharmacology of penile erection. Pharmacol Rev 2001; 53: 417–450.

    CAS  Google Scholar 

  28. Christ GJ, Maayani S, Valcic M, Melman A . Pharmacological studies of human erectile tissue: characteristics of spontaneous contractions and alterations in alpha-adrenoceptor responsiveness with age and disease in isolated tissues. Br J Pharmacol 1990; 101: 375–381.

    Article  CAS  Google Scholar 

  29. McCloskey C, Cagney V, Large R, Hollywood M, Sergeant G, McHale N et al. Voltage-dependent Ca2+ currents contribute to spontaneous Ca2+ waves in rabbit corpus cavernosum myocytes. J Sex Med 2009; 6: 3019–3031.

    Article  CAS  Google Scholar 

  30. Sergeant GP, Johnston L, McHale NG, Thornbury KD, Hollywood MA . Activation of the cGMP/PKG pathway inhibits electrical activity in rabbit urethral interstitial cells of Cajal by reducing the spatial spread of Ca2+ waves. J Physiol 2006; 574: 167–181.

    Article  CAS  Google Scholar 

  31. Sergeant GP, Craven M, Hollywood MA, McHale NG, Thornbury KD . Spontaneous Ca2+ waves in rabbit corpus cavernosum: modulation by nitric oxide and cGMP. J Sex Med 2009; 6: 958–966.

    Article  CAS  Google Scholar 

  32. Hashitani H, Lang RJ . Functions of ICC-like cells in the urinary tract and male genital organs. J Cell Mol Med 2010; 14: 1199–1211.

    Article  CAS  Google Scholar 

  33. Craven M, Sergeant GP, Hollywood MA, McHale NG, Thornbury KD . Modulation of spontaneous Ca2+-activated Cl currents in the rabbit corpus cavernosum by the nitric oxide–cGMP pathway. J Physiol 2004; 556: 495–506.

    Article  CAS  Google Scholar 

  34. Lincoln TM, Dey N, Sellak H . Signal transduction in smooth muscle: invited review: cGMP-dependent protein kinase signaling mechanisms in smooth muscle: from the regulation of tone to gene expression. J Appl Physiol 2001; 91: 1421–1430.

    Article  CAS  Google Scholar 

  35. Adams MA, Brotto LA, Lowenstein L, Brock GB . Survey of literature: current literature review. J Sex Med 2009; 6: 314–317.

    Article  Google Scholar 

  36. Matchkov VV, Aalkjaer C, Nilsson H . A cyclic GMP–dependent calcium-activated chloride current in smooth-muscle cells from rat mesenteric resistance arteries. J Gen Physiol 2004; 123: 121–134.

    Article  CAS  Google Scholar 

  37. Lau LC, Adaikan PG . cGMP regulates chloride efflux in noradrenaline-induced anti-erectile response in corpus cavernosum. J Sex Med 2010; 7 (suppl 4): 157, (Abstract 018).

    Google Scholar 

  38. Eggermont J . Calcium-activated chloride channels: (un)known, (un)loved? Proc Am Thorac Soc 2004; 1: 22–27.

    Article  CAS  Google Scholar 

  39. Oh S, Park J, Han S, Lee J, Roh E, Lee CJ . Development of selective blockers for Ca2+-activated Cl− channel using Xenopus laevis oocytes with an improved drug screening strategy. Mol Brain 2008; 1: 14.

    Article  Google Scholar 

  40. Namkung W, Phuan P, Verkman AS . TMEM16A inhibitors reveal TMEM16A as a minor component of calcium-activated chloride channel conductance in airway and intestinal epithelial cells. J Biol Chem 2010; 286: 2365–2374.

    Article  Google Scholar 

  41. Cunningham SA, Awayda MS, Bubien JK, Ismailov II, Arrate MP, Berdiev BK et al. Cloning of an epithelial chloride channel from bovine trachea. J Biol Chem 1995; 270: 1016–1026.

    Google Scholar 

  42. Kunzelmann K, Milenkovic VM, Spitzner M, Soria RB, Schreiber R . Calcium-dependent chloride conductance in epithelia: is there a contribution by Bestrophin? Pflugers Arch 2007; 454: 879–889.

    Article  CAS  Google Scholar 

  43. Loewen ME, Forsyth GW . Structure and function of CLCA proteins. Physiol Rev 2005; 85: 1061–1092.

    Article  CAS  Google Scholar 

  44. Sun H, Tsunenari T, Yau K, Nathans J . The vitelliform macular dystrophy protein defines a new family of chloride channels. Proc Natl Acad Sci USA 2002; 99: 4008–4013.

    Article  CAS  Google Scholar 

  45. Barro Soria R, Spitzner M, Schreiber R, Kunzelmann K . Bestrophin-1 enables Ca2+-activated Cl- conductance in epithelia. J Biol Chem 2009; 284: 29405–29412.

    Article  CAS  Google Scholar 

  46. Pifferi S, Pascarella G, Boccaccio A, Mazzatenta A, Gustincich S, Menini A et al. Bestrophin-2 is a candidate calcium-activated chloride channel involved in olfactory transduction. Proc Natl Acad Sci USA 2006; 103: 12929–12934.

    Article  CAS  Google Scholar 

  47. Qu Z, Wei RW, Mann W, Hartzell HC . Two bestrophins cloned from Xenopus laevis oocytes express Ca(2+)-activated Cl(−) currents. J Biol Chem 2003; 278: 49563–49572.

    Article  CAS  Google Scholar 

  48. Qu Z, Fischmeister R, Hartzell C . Mouse bestrophin-2 is a bona fide Cl(−) channel: identification of a residue important in anion binding and conduction. J Gen Physiol 2004; 123: 327–340.

    Article  CAS  Google Scholar 

  49. Galietta LJ . The TMEM16 protein family: a new class of chloride channels? Biophys J 2009; 97: 3047–3053.

    Article  CAS  Google Scholar 

  50. Hartzell HC, Yu K, Xiao Q, Chien L, Qu Z . Anoctamin/TMEM16 family members are Ca2+-activated Cl channels. J Physiol 2009; 587: 2127–2139.

    Article  CAS  Google Scholar 

  51. Yu K, Xiao Q, Cui G, Lee A, Hartzell HC . The best disease-linked Cl− channel hBest1 regulates Ca V 1 (L-type) Ca2+ channels via src-homology-binding domains. J Neurosci 2008; 28: 5660–5670.

    Article  CAS  Google Scholar 

  52. Matchkov VV, Larsen P, Bouzinova EV, Rojek A, Boedtkjer DM, Golubinskaya V et al. Bestrophin-3 (vitelliform macular dystrophy 2-like 3 protein) is essential for the cGMP-dependent calcium-activated chloride conductance in vascular smooth muscle cells. Circ Res 2008; 103: 864–872.

    Article  CAS  Google Scholar 

  53. Caputo A, Caci E, Ferrera L, Pedemonte N, Barsanti C, Sondo E et al. TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity. Science 2008; 322: 590–594.

    Article  CAS  Google Scholar 

  54. Schroeder B, Cheng T, Jan Y, Jan L . Expression cloning of TMEM16A as a calcium-activated chloride channel subunit. Cell 2008; 134: 1019–1029.

    Article  CAS  Google Scholar 

  55. Yang YD, Cho H, Koo JY, Tak MH, Cho Y, Shim W et al. TMEM16A confers receptor-activated calcium-dependent chloride conductance. Nature 2008; 455: 1210–1215.

    Article  CAS  Google Scholar 

  56. Kunzelmann K, Kongsuphol P, Aldehni F, Tian Y, Ousingsawat J, Warth R et al. Bestrophin and TMEM16–Ca2+ activated Cl-channels with different functions. Cell Calcium 2009; 46: 233–241.

    Article  CAS  Google Scholar 

  57. Tian Y, Kongsuphol P, Hug M, Ousingsawat J, Witzgall R, Schreiber R et al. Calmodulin-dependent activation of the epithelial calcium-dependent chloride channel TMEM16A. FASEB J 2011; 25: 1058–1068.

    Article  CAS  Google Scholar 

  58. Schreiber R, Uliyakina I, Kongsuphol P, Warth R, Mirza M, Martins JR et al. Expression and function of epithelial anoctamins. J Biol Chem 2010; 285: 7838–7845.

    Article  CAS  Google Scholar 

  59. Manoury B, Tamuleviciute A, Tammaro P . TMEM16A/anoctamin 1 protein mediates calcium-activated chloride currents in pulmonary arterial smooth muscle cells. J Physiol (Lond) 2010; 588: 2305–2314.

    Article  CAS  Google Scholar 

  60. Grasemann H, Ratjen F . Emerging therapies for cystic fibrosis lung disease. Expert Opin Emerg Drugs 2010; 15: 653–659.

    Article  CAS  Google Scholar 

  61. Wang K, Wen FQ, Feng YL, Ou XM, Xu D, Yang J et al. Increased expression of human calcium-activated chloride channel 1 gene is correlated with mucus overproduction in Chinese asthmatic airway. Cell Biol Int 2007; 31: 1388–1395.

    Article  CAS  Google Scholar 

  62. Greenwood IA, Leblanc N . Overlapping pharmacology of Ca2+-activated Cl-and K+ channels. Trends Pharmacol Sci 2007; 28: 1–5.

    Article  CAS  Google Scholar 

  63. Jones K . Review of Sangre de Drago (Croton lechleri)-a South American tree sap in the treatment of diarrhea, inflammation, insect bites, viral infections, and wounds: traditional uses to clinical research. J Altern Complement Med 2003; 9: 877–896.

    Article  Google Scholar 

  64. Tradtrantip L, Namkung W, Verkman AS . Crofelemer, an antisecretory antidiarrheal proanthocyanidin oligomer extracted from croton lechleri, targets two distinct intestinal chloride channels. Mol Pharmacol 2010; 77: 69–78.

    Article  CAS  Google Scholar 

  65. Barrett KE, Keely SJ . Chloride secretion by the intestinal epithelium: molecular basis and regulatory aspects. Annu Rev Physiol 2000; 62: 535–572.

    Article  CAS  Google Scholar 

  66. De La Fuente R, Namkung W, Mills A, Verkman AS . Small-molecule screen identifies inhibitors of a human intestinal calcium-activated chloride channel. Mol Pharmacol 2008; 73: 758–768.

    Article  CAS  Google Scholar 

  67. Namkung W, Finkbeiner WE, Verkman AS . CFTR-adenylyl cyclase I association responsible for UTP activation of CFTR in well-differentiated primary human bronchial cell cultures. Mol Biol Cell 2010; 21: 2639–2648.

    Article  CAS  Google Scholar 

  68. Liang L, MacDonald K, Schwiebert EM, Zeitlin PL, Guggino WB . Spiperone, identified through compound screening, activates calcium-dependent chloride secretion in the airway. Am J Physiol Cell Physiol 2009; 296: C131–C141.

    Article  CAS  Google Scholar 

  69. Namkung W, Thiagarajah JR, Phuan PW, Verkman AS . Inhibition of Ca2+-activated Cl− channels by gallotannins as a possible molecular basis for health benefits of red wine and green tea. FASEB J 2010; 24: 4178–4186.

    Article  CAS  Google Scholar 

  70. Rock JR, Futtner CR, Harfe BD . The transmembrane protein TMEM16A is required for normal development of the murine trachea. Dev Biol 2008; 321: 141–149.

    Article  CAS  Google Scholar 

  71. Azadzoi K, Schulman R, Aviram M, Siroky M . Oxidative stress in arteriogenic erectile dysfunction: prophylactic role of antioxidants. J Urol 2005; 174: 386–393.

    Article  CAS  Google Scholar 

  72. Zhang Q, Radisavljevic ZM, Siroky MB, Azadzoi KM . Dietary antioxidants improve arteriogenic erectile dysfunction. Int J Androl 2010; 33: 1–11.

    Google Scholar 

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Acknowledgements

Exchange student fellowship for DJL from the University of British Columbia, Canada to the Department of OBGYN, National University of Singapore was supported by a grant from Lee Foundation, Singapore.

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  1. Department of Anaesthiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada

    D J Linton

  2. Department of Obstetrics and Gynaecology, Yong Loo Lin School of Medicine, National University Hospital, Singapore

    L C Lau & P G Adaikan

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Linton, D., Lau, L. & Adaikan, P. Calcium-activated chloride channels in the corpus cavernosum: recent developments and future of a key cellular component of the erectile process. Int J Impot Res 24, 211–216 (2012). https://doi.org/10.1038/ijir.2012.22

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