Ion Channels and Intracellular Calcium Signalling in Corpus Cavernosum

  • Keith D. ThornburyEmail author
  • Mark A. Hollywood
  • Gerard P. Sergeant
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1124)


The corpus cavernosum smooth muscle is important for both erection of the penis and for maintaining penile flaccidity. Most of the time, the smooth muscle cells are in a contracted state, which limits filling of the corpus sinuses with blood. Occasionally, however, they relax in a co-ordinated manner, allowing filling to occur. This results in an erection. When contractions of the corpus cavernosum are measured, it can be deduced that the muscle cells work together in a syncytium, for not only do they spontaneously contract in a co-ordinated manner, but they also synchronously relax. It is challenging to understand how they achieve this.

In this review we will attempt to explain the activity of the corpus cavernosum, firstly by summarising current knowledge regarding the role of ion channels and how they influence tone, and secondly by presenting data on the intracellular Ca2+ signals that interact with the ion channels. We propose that spontaneous Ca2+ waves act as a primary event, driving transient depolarisation by activating Ca2+-activated Cl channels. Depolarisation then facilitates Ca2+ influx via L-type voltage-dependent Ca2+ channels. We propose that the spontaneous Ca2+ oscillations depend on Ca2+ release from both ryanodine- and inositol trisphosphate (IP3)-sensitive stores and that modulation by signalling molecules is achieved mainly by interactions with the IP3-sensitive mechanism. This pacemaker mechanism is inhibited by nitric oxide (acting through cyclic GMP) and enhanced by noradrenaline. By understanding these mechanisms better, it might be possible to design new treatments for erectile dysfunction.


Corpus cavernosum Smooth muscle Calcium waves Calcium imaging STICs STOCS STDs 



The authors are grateful for grant support from the Wellcome Trust (064212), NIH (RO1 DK68565), Health Research Board (PD/2005/4 and RP/2006/127), Enterprise Ireland (ARE20080001 and CE20080020) Diabetes UK, Science Foundation Ireland (BIMF377) and IOTI. We wish also to thank Ms Billie McIlveen for technical support.

Supplementary material

Supplementary Movie 7.1

Effect of sildenafil (1 μM) on spontaneous Ca2+ waves in a corpus cavernosum Corpus cavernosum myocyte isolated from rabbit. There are 28 s of control recording, where the cell fires spontaneous Ca2+ waves, before sildenafil is added. Sildenafil inhibits the Ca2+ waves. Note, however, two ‘breakthrough’ Ca2+ events that appear before washout of sildenafil. After washout, normal activity returns. Cell was loaded with fluo-4AM and studied with a Nipkow spinning disk laser confocal system coupled to an EMCCD camera. Images were acquired at 5 frames per second. Scale: cell is approximately 80 μm in length. Pseudo-linescan of this movie is published in reference [77], Fig. 7.4a (MOV 6023 kb)

Supplementary Movie 7.2

Spontaneous Ca2+ waves events in a whole tissue preparation of rabbit corpus cavernosum. At the beginning, the sinuses are relaxed. This is followed by bursts of spontaneous phasic Ca2+ events associated with contractions of the smooth muscle trabeculae. The Ca2+ events spread across the trabeculae of four sinuses, causing contraction and narrowing of the sinuses. The spread was too fast to allow measurement of conduction velocity at the image acquisition rate of 5 frames per second; however, it is clear that the corpus cavernosum smooth muscle cells are very well coupled. Tissue was loaded with fluo-4AM and studied with a Nipkow spinning disk laser confocal system coupled to an EMCCD camera. Contractions occurred despite partial immobilisation by a combination of pinning and low dose (1.25 μM) wortmannin, a myosin light chain kinase inhibitor (MLCK). Scale: relaxed sinuses are approximately 50 μm in diameter. Frames from this movie are published in reference [77], Fig. 7.5a (MOV 8472 kb).

Supplementary Movie 7.3

Effect of sildenafil (1 μM) in a whole tissue preparation of rabbit corpus cavernosum. Two trabeculae are shown, with Ca2+ events occurring independently in each. In the trabeculum on the left, fast Ca2+ events similar to those in Movie 7.2 are seen, but slower Ca2+ waves may be observed on the right. Sildenafil completely inhibits the fast activity, though some slow Ca2+ waves continue to occur in the presence of the drug. Recording conditions as Movie 7.2. Scale: frame is approximately 240 μM square. Frames and plots from this movie are published in reference [77], Fig. 7.5b, c (MOV 16174 kb)


  1. 1.
    Doyle C. Characterisation of interstitial cells of cajal and smooth muscle cells in the corpus cavernosum. PhD thesis, Dundalk Institute of Technology, Dundalk, Co Louth; 2011.Google Scholar
  2. 2.
    Andersson KE, Wagner G. Physiology of penile erection. Physiol Rev. 1995;75:191–236.PubMedCrossRefGoogle Scholar
  3. 3.
    Andersson KE. Pharmacology of penile erection. Pharmacol Rev. 2001;53:417–50.PubMedGoogle Scholar
  4. 4.
    Shamloul R, Ghanem H. Erectile dysfunction. Lancet. 2013;381:153–65.PubMedCrossRefGoogle Scholar
  5. 5.
    Hawksworth DJ, Burnett AL. Pharmacotherapeutic management of erectile dysfunction. Clin Pharmacol Ther. 2015;98(6):602–10.PubMedCrossRefGoogle Scholar
  6. 6.
    Campos de Carvalho AC, Roy C, Moreno AP, Melman A, Hertzberg EL, Christ GJ, Spray DC. Gap junctions formed of connexin43 are found between smooth muscle cells of human corpus cavernosum. J Urol. 1993;149(6):1568–75.PubMedCrossRefGoogle Scholar
  7. 7.
    Hannigan K. Regulation of corpus cavernosum activity by ion channel modulators. PhD Thesis, Dundalk Institute of Technology, Dundalk, Co Louth; 2016.Google Scholar
  8. 8.
    Moreno AP, Campos de Carvalho AC, Christ G, Melman A, Spray DC. Gap junctions between human corpus cavernosum smooth muscle cells: gating properties and unitary conductance. Am J Phys. 1993;264:C80–92.CrossRefGoogle Scholar
  9. 9.
    Hashitani H, Yanai Y, Shirasawa N, Soji T, Tomita A, Kohri K, Suzuki H. Interaction between spontaneous and neurally mediated regulation of smooth muscle tone in the rabbit corpus cavernosum. J Physiol. 2005;569:723–35.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Hannigan KI, Large RJ, Bradley E, Hollywood MA, Sergeant GP, McHale NG, Thornbury KD. Effect of a novel BKCa opener on BKCa currents and contractility of the rabbit corpus cavernosum. Am J Phys Cell Physiol. 2016;310:C284–92.CrossRefGoogle Scholar
  11. 11.
    Mizusawa H, Hedlund P, Håkansson A, Alm P, Andersson KE. Morphological and functional in vitro and in vivo characterization of the mouse corpus cavernosum. Br J Pharmacol. 2001;132:1333–41.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Werner ME, Meredith AL, Aldrich RW, Nelson MT. Hypercontractility and impaired sildenafil relaxations in the BKCa deletion model of erectile dysfunction. Am J Phys Regul Integr Comp Phys. 2008;295:181–8.Google Scholar
  13. 13.
    Fovaeus M, Andersson K-E, Hedlund H. Effects of some calcium channel blockers on isolated human penile erectile tissue. J Urol. 1987;138:1267–72.PubMedCrossRefGoogle Scholar
  14. 14.
    Hoppner CK, Stief CG, Jonas U, Mandrek K, Noack T, Golenhofen K. Electrical and chemical control of smooth muscle activity of rabbit corpus cavernosum in vitro. Urology. 1996;48(5):12–5 18.Google Scholar
  15. 15.
    McCloskey C, Cagney V, Large R, Hollywood M, Sergeant G, McHale N, Thornbury K. Voltage-dependent Ca2+ currents contribute to spontaneous Ca2+ waves in rabbit corpus cavernosum myocytes. J Sex Med. 2009;6:3019–31.PubMedCrossRefGoogle Scholar
  16. 16.
    Imaizumi Y, Muraki K, Takeda M, Watanabe M. Measurement and simulation of noninactivating Ca current in smooth muscle cells. Am J Phys. 1989;256:C880–5.CrossRefGoogle Scholar
  17. 17.
    Smirnov SV, Aaronson PI. Ca2+ currents in single myocytes from human mesenteric arteries: evidence for a physiological role of L-type channels. J Physiol. 1992;457:455–75.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Christ GJ, Hodges S. Molecular mechanisms of detrusor and corporal myocyte contraction: identifying targets for pharmacotherapy of bladder and erectile dysfunction. Br J Pharmacol. 2006;147(Suppl 2):S41–55.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Doyle C, Sergeant GP, Hollywood MA, McHale NG, Thornbury KD. Effects of phenylephrine on spontaneous activity and L-type Ca2+ current in isolated corpus cavernosum myocytes. J Sex Med. 2012;9:2795–805.PubMedCrossRefGoogle Scholar
  20. 20.
    Keef KD, Hume JR, Zhong J. Regulation of cardiac and smooth muscle Ca2+ channels (CaV1.2a,b) by protein kinases. Am J Phys. 2001;281:C1743–56.CrossRefGoogle Scholar
  21. 21.
    Perez-Reyes E. Molecular physiology of low voltage-activated T-type calcium channels. Physiol Rev. 2003;83:117–61.PubMedCrossRefGoogle Scholar
  22. 22.
    Zeng X, Keyser B, Li M, Sikka SC. T-type (alpha1G) low voltage-activated calcium channel interactions with nitric oxide-cyclic guanosine monophosphate pathway and regulation of calcium homeostasis in human cavernosal cells. J Sex Med. 2005;2:620–30.PubMedCrossRefGoogle Scholar
  23. 23.
    House SJ, Potier M, Bisaillon J, Singer HA, Trebak M. The non-excitable smooth muscle: calcium signaling and phenotypic switching during vascular disease. Pflugers Arch. 2008;456:769–85.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    North RA. Molecular physiology of P2X receptors. Physiol Rev. 2002;82:1013–67.PubMedCrossRefGoogle Scholar
  25. 25.
    Sneddon P, Burnstock G. Inhibition of excitatory junction potentials in guinea-pig vas deferens by alpha, beta-methylene- ATP: further evidence for ATP and noradrenaline as cotransmitters. Eur J Pharmacol. 1984;100:85–90.PubMedCrossRefGoogle Scholar
  26. 26.
    Sneddon P, Burnstock G. ATP as a co-transmitter in rat tail artery. Eur J Pharmacol. 1984;106:149–52.PubMedCrossRefGoogle Scholar
  27. 27.
    Phatarpekar PV, Wen J, Xia Y. Role of adenosine signaling in penile erection and erectile disorders. J Sex Med. 2010;7:3553–64.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Staerman F, Shalev M, Legrand A, Lobel B, Saïag B. P2Y and P2X purinoceptors are respectively implicated in endothelium-dependent relaxation and endothelium independent contraction in human corpus cavernosum. Adv Exp Med Biol. 2000;486:189–95.PubMedCrossRefGoogle Scholar
  29. 29.
    Wu HY, Broderick GA, Suh JK, Hypolite JA, Levin RM. Effects of purines on rabbit corpus cavernosum contractile activity. Int J Impot Res. 1993;5:161–7.PubMedGoogle Scholar
  30. 30.
    Doyle C, Sergeant GP, Hollywood MA, McHale NG, Thornbury KD. ATP evokes inward currents in corpus cavernosum myocytes. J Sex Med. 2014;11(1):64–74.PubMedCrossRefGoogle Scholar
  31. 31.
    Lee HY, Bardini M, Burnstock G. P2X receptor immunoreactivity in the male genital organs of the rat. Cell Tissue Res. 2000;300:321–30.PubMedCrossRefGoogle Scholar
  32. 32.
    Suadicani SO, Urban-Maldonado M, Tar MT, Melman A, Spray DC. Effects of ageing and streptozotocin-induced diabetes on connexin43 and P2 purinoceptor expression in the rat corpora cavernosa and urinary bladder. BJU Int. 2009;103:1686–93.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Gur S, Kadowitz PJ, Abdel-Mageed AB, Kendirci M, Sikka SC, Burnstock G, Hellstrom WJ. Management of erectile function by penile purinergic p2 receptors in the diabetic rat. J Urol. 2009;181:2375–82.PubMedCrossRefGoogle Scholar
  34. 34.
    Yue Z, Xie J, Yu AS, Stock J, Du J, Yue L. Role of TRP channels in the cardiovascular system. Am J Physiol Heart Circ Physiol. 2015;308:H157–82.PubMedCrossRefGoogle Scholar
  35. 35.
    Earley S. TRPM4 channels in smooth muscle function. Pflugers Arch. 2013;465:1223–31.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Latorre R, Castillo K, Carrasquel-Ursulaez W, Sepulveda RV, Gonzalez-Nilo F, Gonzalez C, Alvarez O. Molecular determinants of BK channel functional diversity and functioning. Physiol Rev. 2017;97:39–87.PubMedCrossRefGoogle Scholar
  37. 37.
    Knaus HG, McManus OB, Lee SH, Schmalhofer WA, Garcia-Calvo M, Helms LM, Sanchez M, Giangiacomo K, Reuben JP, Smith AB 3rd, et al. Tremorgenic indole alkaloids potently inhibit smooth muscle high-conductance calcium-activated potassium channels. Biochemistry. 1994;3319:5819–28.CrossRefGoogle Scholar
  38. 38.
    Yan J, Aldrich RW. LRRC26 auxiliary protein allows BK channel activation at resting voltage without calcium. Nature. 2010;466:513–6.PubMedCrossRefGoogle Scholar
  39. 39.
    Kshatri AS, Li Q, Yan J, Large RJ, Sergeant GP, McHale NG, Thornbury KD, Hollywood MA. Differential efficacy of GoSlo-SR compounds on BKα and BKαγ(1-4) channels. Channels (Austin). 2017;11:66–78.CrossRefGoogle Scholar
  40. 40.
    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(1):301–13.PubMedCrossRefGoogle Scholar
  41. 41.
    Lee SW, Kang TM. Effects of nitric oxide on the Ca2+-activated potassium channels in smooth muscle cells of the human corpus cavernosum. Urol Res. 2001;29:359–65.PubMedCrossRefGoogle Scholar
  42. 42.
    Craven M. Regulation of rabbit corpus cavernosum smooth muscle. PhD Thesis, Queen’s University of Belfast, Belfast; 2006.Google Scholar
  43. 43.
    Nelson MT, Cheng H, Rubart M, Santana LF, Bonev AD, Knot HJ, Lederer WJ. Relaxation of arterial smooth muscle by calcium sparks. Science. 1995;270:633–7.CrossRefGoogle Scholar
  44. 44.
    Werner ME, Zvara P, Meredith AL, Aldrich RW, Nelson MT. Erectile dysfunction in mice lacking the large-conductance calcium-activated potassium (BK) channel. J Physiol. 2005;567:545–56.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Bolotina VM, Najibi S, Palacino JJ, Pagano PJ, Cohen RA. Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle. Nature. 1994;368(6474):850–3.PubMedCrossRefGoogle Scholar
  46. 46.
    Lang RJ, Harvey JR, McPhee GJ, Klemm MF. Nitric oxide and thiol reagent modulation of Ca2+-activated K+ (BKCa) channels in myocytes of the guinea-pig taenia caeci. J Physiol. 2000;525:363–76.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    McCloskey C. Electrical activity in isolated cells of rabbit corpus cavernosum. PhD Thesis, Queen’s University of Belfast, Belfast; 2007.Google Scholar
  48. 48.
    Alioua A, Tanaka Y, Wallner M, Hofmann F, Ruth P, Meera P, Toro L. The large conductance, voltage-dependent, and calcium-sensitive K+ channel, Hslo, is a target of cGMP-dependent protein kinase phosphorylation in vivo. J Biol Chem. 1998;273:32950–6.PubMedCrossRefGoogle Scholar
  49. 49.
    Fukao M, Mason HS, Britton FC, Kenyon JL, Horowitz B, Keef KD. Cyclic GMP-dependent protein kinase activates cloned BKCa channels expressed in mammalian cells by direct phosphorylation at serine 1072. J Biol Chem. 1999;274:10927–35.PubMedCrossRefGoogle Scholar
  50. 50.
    Zhou X-B, Schlossmann J, Hofmann F, Ruth P, Korth M. Regulation of stably expressed and native BK channels from human myometrium by cGMP- and cAMP-dependent protein kinase. Pflugers Arch. 1998;436:725–34.PubMedCrossRefGoogle Scholar
  51. 51.
    Zhou XB, Arntz C, Kamm S, Motejlek K, Sausbier U, Wang GX, Ruth P, Korth M. A molecular switch for specific stimulation of the BKCa channel by cGMP and cAMP kinase. J Biol Chem. 2001;276:43239–45.PubMedCrossRefGoogle Scholar
  52. 52.
    Porter VA, Bonev AD, Knot HJ, Heppner TJ, Stevenson AS, Kleppisch T, Lederer WJ, Nelson MT. Frequency modulation of Ca2 sparks is involved in regulation of arterial diameter by cyclic nucleotides. Am J Phys. 1998;274:C1346–55.CrossRefGoogle Scholar
  53. 53.
    Wellman GC, Santana LF, Bonev AD, Nelson MT. Role of phospholamban in the modulation of arterial Ca2+sparks and Ca2+ activated K+ channels by cAMP. Am J Phys. 2001;281:C1029–37.CrossRefGoogle Scholar
  54. 54.
    Eggermont JA, Vrolix M, Wuytack F, Raeymaekers L, Casteels R. The Ca2+-Mg2+-ATPases of the plasma membrane and of the endoplasmic reticulum in smooth muscle cells and their regulation. J Cardiovasc Pharmacol. 1988;1(2 Suppl 5):S51–5.CrossRefGoogle Scholar
  55. 55.
    Joshi S, Nelson MT, Werner ME. Amplified NO/cGMP-mediated relaxation and ryanodine receptor-to-BKCa channel signalling in corpus cavernosum smooth muscle from phospholamban knockout mice. Br J Pharmacol. 2012;1652:455–66.CrossRefGoogle Scholar
  56. 56.
    Kun A, Matchkov VV, Stankevicius E, Nardi A, Hughes AD, Kirkeby HJ, Demnitz J, Simonsen U. NS11021, a novel opener of large-conductance Ca2+-activated K+ channels, enhances erectile responses in rats. Br J Pharmacol. 2009;158:1465–76.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Király I, Pataricza J, Bajory Z, Simonsen U, Varro A, Papp JG, Pajor L, Kun A. Involvement of large-conductance Ca2+-activated K+ channels in both nitric oxide and endothelium-derived hyperpolarization-type relaxation in human penile small arteries. Basic Clin Pharmacol Toxicol. 2013;113:19–24.PubMedCrossRefGoogle Scholar
  58. 58.
    Boy KM, Guernon JM, Sit SY, Xie K, Hewawasam P, Boissard CG, Dworetzky SI, Natale J, Gribkoff VK, Lodge N, Starrett JE Jr. 3-Thio-quinolinone maxi-K openers for the treatment of erectile dysfunction. Bioorg Med Chem Lett. 2004;14:5089–93.PubMedCrossRefGoogle Scholar
  59. 59.
    Hewawasam P, Fan W, Cook DA, Newberry KS, Boissard CG, Gribkoff VK, Starrett J, Lodge NJ. 4-Aryl-3-(mercapto)quinolin-2-ones: novel maxi-K channel opening relaxants of corporal smooth muscle. Bioorg Med Chem Lett. 2004;14:4479–82.PubMedCrossRefGoogle Scholar
  60. 60.
    Roy S, Morayo Akande A, Large RJ, Webb TI, Camarasu C, Sergeant GP, McHale NG, Thornbury KD, Hollywood MA. Structure-activity relationships of a novel group of large-conductance Ca2+-activated K+ (BK) channel modulators: the GoSlo-SRFamily. ChemMedChem. 2012;7(10):1763–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Large RJ, Kshatri A, Webb TI, Roy S, Akande A, Bradley E, Sergeant GP, Thornbury KD, McHale NG, Hollywood MA. Effects of the novel BK channel opener GoSlo-SR-5-130 are dependent on the presence of BK β subunits. Br J Pharmacol. 2015;172:2544–56.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Yoshimura N, Kato R, Chancellor MB, Nelson JB, Glorioso JC. Gene therapy as future treatment of erectile dysfunction. Expert Opin Biol Ther. 2010;10:1305–14.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Christ GJ, Rehman J, Day N, Salkoff L, Valcic M, Melman A, Geliebter J. Intracorporal injection of hSlo cDNA in rats produces physiologically relevant alterations in penile function. Am J Phys. 1998;275:H600–8.Google Scholar
  64. 64.
    Christ GJ, Day N, Santizo C, Sato Y, Zhao W, Sclafani T, Bakal R, Salman M, Davies K, Melman A. Intracorporal injection of hSlo cDNA restores erectile capacity in STZ-diabetic F-344 rats in vivo. Am J Phys. 2004;287:H1544–53.Google Scholar
  65. 65.
    Melman A, Zhao W, Davies KP, Bakal R, Christ GJ. The successful long-term treatment of age related erectile dysfunction with hSlo cDNA in rats in vivo. J Urol. 2003;170:285–90.PubMedCrossRefGoogle Scholar
  66. 66.
    Melman A, Bar-Chama N, McCullough A, Davies K, Christ G. hMaxi-K gene transfer in males with erectile dysfunction: results of the first human trial. Hum Gene Ther. 2006;18:1165–76.CrossRefGoogle Scholar
  67. 67.
    Christ GJ, Andersson KE, Williams K, Zhao W, D’Agostino R Jr, Kaplan J, Aboushwareb T, Yoo J, Calenda G, Davies KP, Sellers RS, Melman A. Smooth-muscle-specific gene transfer with the human maxi-k channel improves erectile function and enhances sexual behavior in atherosclerotic cynomolgus monkeys. Eur Urol. 2009;56:1055–66.PubMedCrossRefGoogle Scholar
  68. 68.
    Malysz J, Gibbons SJ, Miller SM, Gettman M, Nehra A, Szurszewski JH, Farrugia G. Potassium outward currents in freshly dissociated rabbit corpus cavernosum myocytes. J Urol. 2001;166:1167–77.PubMedCrossRefGoogle Scholar
  69. 69.
    Malysz J, Farrugia G, Ou Y, Szurszewski JH, Nehra A, Gibbons SJ. The Kv2.2 alpha subunit contributes to delayed rectifier K(+) currents in myocytes fromrabbit corpus cavernosum. J Androl. 2002;23:899–910.PubMedGoogle Scholar
  70. 70.
    Jepps TA, Olesen SP, Greenwood IA, Dalsgaard T. Molecular and functional characterization of Kv 7 channels in penile arteries and corpus cavernosum of healthy and metabolic syndrome rats. Br J Pharmacol. 2016;173:1478–90.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Ashcroft FM, Gribble FM. Correlating structure and function in ATP-sensitive K+ channels. Trends Neurosci. 1998;21:288–94.PubMedCrossRefGoogle Scholar
  72. 72.
    Nelson MT. Ca2+-activated potassium channels and ATP-sensitive potassium channels as modulators of vascular tone. Trends Cardiovasc Med. 1993;3:54–60.PubMedCrossRefGoogle Scholar
  73. 73.
    Insuk SO, Chae MR, Choi JW, DK Yang DK, Sim JH, Lee SW. Molecular basis and characteristics of KATP channel in human corporal smooth muscle cells. Int J Impot Res. 2003;15:258–66.PubMedCrossRefGoogle Scholar
  74. 74.
    Large WA, Wang Q. Characteristics and physiological role of the Ca2+-activated Cl conductance in smooth muscle. Am J Phys. 1996;271:C435–54.CrossRefGoogle Scholar
  75. 75.
    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;566:495–506.CrossRefGoogle Scholar
  76. 76.
    Williams BA, Sims SM. Calcium sparks activate calcium-dependent Cl current in rat corpus cavernosum smooth muscle cells. Am J Phys. 2007;293:C1239–51.CrossRefGoogle Scholar
  77. 77.
    Sergeant GP, Craven M, Hollywood MA, McHale NG, Thornbury KD. Spontaneous Ca2+ waves in isolated myocytes from rabbit corpus cavernosum: modulation by the NO/cGMP pathway. J Sex Med. 2009;6:958–66.PubMedCrossRefGoogle Scholar
  78. 78.
    Hannigan KI, Griffin CS, Large RL, Sergeant GP, Hollywood MA, McHale NG, Thornbury KD. The role of Ca2+-activated Cl current in tone generation in the rabbit corpus cavernosum. Am J Phys. 2017;313:C475–86.CrossRefGoogle Scholar
  79. 79.
    Caputo A, Caci E, Ferrera L, Pedemonte N, Barsanti C, Sondo E, Pfeffer U, Ravazzolo R, Zegarra-Moran O, Galietta LJ. TMEM16A, a membrane protein associated with calcium-dependent chloride channel activity. Science. 2008;322:590–4.CrossRefGoogle Scholar
  80. 80.
    Schroeder BC, Cheng T, Jan YN, Jan LY. Expression cloning of TMEM16A as a calcium-activated chloride channel subunit. Cell. 2008;134:1019–29.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Yang YD, Cho H, Koo JY, Tak MH, Cho Y, Shim WS, Park SP, Lee J, Lee B, Kim BM, Raouf R, Shin YK, Oh U. TMEM16A confers receptor-activated calcium-dependent chloride conductance. Nature. 2008;455:1210–5.CrossRefGoogle Scholar
  82. 82.
    Ferrera L, Caputo A, Ubby I, Bussani E, Zegarra-Moran O, Ravazzolo R, Pagani F, Galietta LJ. Regulation of TMEM16A chloride channel properties by alternative splicing. J Biol Chem. 2009;284:33360–8.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Chipperfield AR, Harper AA. Chloride in smooth muscle. Prog Biophys Mol Biol. 2000;74:175–221.PubMedCrossRefGoogle Scholar
  84. 84.
    Chu LL, Adaikan PG. Role of chloride channels in the regulation of corpus cavernosum tone: a potential therapeutic target for erectile dysfunction. J Sex Med. 2008;5:813–21.PubMedCrossRefGoogle Scholar
  85. 85.
    Lau LC, Adaikan PG. Possibility of inhibition of calcium-activated chloride channel rescuing erectile failures in diabetes. Int J Impot Res. 2014;264:151–5.CrossRefGoogle Scholar
  86. 86.
    Hashitani H. Neuroeffector transmission to different layers of smooth muscle in the rat penile bulb. J Physiol. 2000;524:549–63.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Van Helden DF. Spontaneous and noradrenaline-induced transient depolarizations in the smooth muscle of guinea-pig mesenteric vein. J Physiol. 1991;437:511–41.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Cotton KD, Hollywood MA, McHale NG, Thornbury KD. Ca2+-current and Ca2+-activated chloride current in isolated smooth muscle cells of the sheep urethra. J Physiol. 1997;505:121–31.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Williams BA, Liu C, DeYoung L, Brock GB, Sims SM. Regulation of intracellular Ca2+ release in corpus cavernosum smooth muscle: synergism between nitric oxide and cGMP. Am J Phys. 2005;288:C650–8.CrossRefGoogle Scholar
  90. 90.
    Jaggar JH, Porter VA, Lederer WJ, Nelson MT. Calcium sparks in smooth muscle. Am J Phys. 2000;27:C235–56.CrossRefGoogle Scholar
  91. 91.
    Gordienko DV, Bolton TB. Crosstalk between ryanodine receptors and IP3 receptors as a factor shaping spontaneous Ca2+-release events in rabbit portal vein myocytes. J Physiol. 2002;542:743–62.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Drumm BT, Large RJ, Hollywood MA, Thornbury KD, Baker SA, Harvey BJ, McHale NG, Sergeant GP. The role of Ca2+ influx in spontaneous Ca2+wave propagation in interstitial cells of Cajal from the rabbit urethra. J Physiol. 2015;593:3333–50.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Wang H, Eto M, Steers WD, Somlyo AP, Somlyo AV. RhoA-mediated Ca2+ sensitization in erectile function. J Biol Chem. 2002;277:30614–21.PubMedCrossRefGoogle Scholar
  94. 94.
    Hashitani H. Interaction between interstitial cells and smooth muscles in the lower urinary tract and penis. J Physiol. 2006;576:707–14.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Schlossmann J, Ammendola A, Ashman K, Zong X, Huber A, Neubauer G, Wang GX, Allescher HD, Korth M, Wilm M, Hofmann F, Ruth P. Regulation of intracellular calcium by a signalling complex of IRAG, IP3 receptor and cGMP kinase Ibeta. Nature. 2000;404:197–201.PubMedCrossRefGoogle Scholar
  96. 96.
    Feil R, Gappa N, Rutz M, Schlossmann J, Rose CR, Konnerth A, Brummer S, Kuhbandner S, Hofmann F. Functional reconstitution of vascular smooth muscle cells with cGMP-dependent protein kinase I isoforms. Circ Res. 2002;90:1080–6.PubMedCrossRefGoogle Scholar
  97. 97.
    Ruth P, Wang GX, Boekhoff I, May B, Pfeifer A, Penner R, Korth M, Breer H, Hofmann F. Transfected cGMP-dependent protein kinase suppresses calcium transients by inhibition of inositol 1,4,5-trisphosphate production. Proc Natl Acad Sci U S A. 1993;90:2623–7.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Keith D. Thornbury
    • 1
    Email author
  • Mark A. Hollywood
    • 1
  • Gerard P. Sergeant
    • 1
  1. 1.Smooth Muscle Research Centre, Regional Development CentreDundalk Institute of TechnologyDundalkIreland

Personalised recommendations