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

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.