KV7 channels in the human detrusor: channel modulator effects and gene and protein expression

Abstract

Voltage-gated type 7 K⁺ (K_V7 or KCNQ) channels regulate the contractility of various smooth muscles. With this study, we aimed to assess the role of K_V7 channels in the regulation of human detrusor contractility, as well as the gene and protein expression of K_V7 channels in this tissue. For these purposes, the isolated organ technique, RT-qPCR, and Western blot were used, respectively. XE-991, a selective K_V7 channel blocker, concentration-dependently contracted the human detrusor; mean EC₅₀ and E_max of XE-991-induced concentration-response curve were 14.1 μM and 28.8 % of the maximal bethanechol-induced contraction, respectively. Flupirtine and retigabine, selective K_V7.2-7.5 channel activators, induced concentration-dependent relaxations of bethanechol-precontracted strips, with maximal relaxations of 51.6 and 51.8 % of the precontraction, respectively. XE-991 blocked the relaxations induced by flupirtine and retigabine. All five KCNQ genes were found to be expressed in the detrusor with KCNQ4 being the most expressed among them. Different bands, having sizes similar to some of reported K_V7.1, 7.4, and 7.5 channel subunit isoforms, were detected in the detrusor by Western blot with the K_V7.4 band being the most intense among them. In conclusion, K_V7 channels contribute to set the basal tone of the human detrusor. In addition, K_V7 channel activators significantly relax the detrusor. The K_V7.4 channels are probably the most important K_V7 channels expressed in the human detrusor. These data suggest that selective K_V7.4 channel activators might represent new pharmacological tools for inducing therapeutic relaxation of the detrusor.

Keywords: Flupirtine; Human detrusor; KCNQ channels; KV7 channels; Retigabine; XE-991.