Ion Channels and Intracellular Calcium Signalling in Corpus Cavernosum
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.
KeywordsCorpus 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.
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 , Fig. 7.4a (MOV 6023 kb)
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 , Fig. 7.5a (MOV 8472 kb).
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 , Fig. 7.5b, c (MOV 16174 kb)
- 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
- 7.Hannigan K. Regulation of corpus cavernosum activity by ion channel modulators. PhD Thesis, Dundalk Institute of Technology, Dundalk, Co Louth; 2016.Google Scholar
- 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
- 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
- 42.Craven M. Regulation of rabbit corpus cavernosum smooth muscle. PhD Thesis, Queen’s University of Belfast, Belfast; 2006.Google Scholar
- 47.McCloskey C. Electrical activity in isolated cells of rabbit corpus cavernosum. PhD Thesis, Queen’s University of Belfast, Belfast; 2007.Google Scholar
- 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
- 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
- 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.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
- 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