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 K_V7 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 K_V7-encoding gene. Immunocytochemistry in single CCSM myocytes confirmed expression of K_V7.5 protein. CCSM crura developed spontaneous phasic contractions in vitro that were inhibited by retigabine (RTG), a K_V7 channel opener, and potentiated by XE-991, a K_V7 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 K_V7 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 K_V7 channel modulators, whereas tonic contractions and Ca²⁺ signals induced by high concentrations of PE are resistant to these compounds. This provides hope that K_V7 channels may be targeted to treat ED.