KV7 channels modulate tension and calcium signaling in mouse corpus cavernosum.

Adrenergic stimulation induces contractions in the corpus cavernosum smooth muscle (CCSM), which are important in maintaining penile flaccidity. The aim of this study was to investigate the role of KV7 channels in regulating contractions and their underlying Ca2+ signals in mouse CCSM. Quantitative PCR revealed transcriptional expression of KCNQ1 and KCNQ3-5 genes in the whole CCSM, with KCNQ5 as the most highly transcribed KV7-encoding gene. Immunocytochemistry in single CCSM myocytes confirmed expression of KV7.5 protein. CCSM crura developed spontaneous phasic contractions in vitro that were inhibited by retigabine (RTG), a KV7 channel opener, and potentiated by XE-991, a KV7 channel blocker. The contractions were also blocked by nifedipine, confirming that they were dependent upon Ca2+ influx via L-type Ca2+ channels. Similarly, phenylephrine (PE) (0.3 µM) evoked phasic contractions that were inhibited and enhanced by RTG and XE-991, respectively. When a range of concentrations of PE (0.1-30 µM) was examined, both phasic and tonic contractions were observed, with phasic predominating at lower concentrations and tonic at higher concentrations. RTG inhibited only the phasic contractions, suggesting that these were dependent upon membrane potential but tonic contractions were not. In single-dispersed CCSM myocytes, spontaneous Ca2+ waves and Ca2+ waves induced by PE (0.1 µM) were inhibited by RTG or nifedipine and enhanced by XE-991. PE (10 µM) also induced Ca2+ waves but, similar to tonic contractions, these were resistant to inhibition with RTG or nifedipine. These findings have implications for targeting KV7 channels in the treatment of erectile dysfunction.NEW & NOTEWORTHY Many men with ED are resistant to treatment with phosphodiesterase 5 inhibitors (e.g., sildenafil); therefore, new treatments are required. We show that spontaneous contractions and phasic contractions of CCSM induced by low/moderate concentrations of PE, and their underlying Ca2+ signals, are altered by KV7 channel modulators, whereas tonic contractions and Ca2+ signals induced by high concentrations of PE are resistant to these compounds. This provides hope that KV7 channels may be targeted to treat ED.