Regulation of Kv7 Channel Function in Rat Bladder by ERα and GPER1 Estrogen Receptors

This study investigated the sex and oestrous-stage dependent effects on voltage-gated potassium channels encoded by KCNQ genes (Kv7) channels in the rat bladder, focusing on the roles of different estrogen receptors (ERs). We hypothesized that ERα and G-protein-coupled estrogen receptor (GPER1) play distinct roles in modulating Kv7.4 and Kv7.5 channel functionality and localization. Using bladder tissues from male and female Wistar rats at different oestrous stages, we performed myography, RT-qPCR, immunocytochemistry, and western blot analyses. Our results showed that ML213, a Kv7.2-7.5 activator, was more effective in male bladders, correlating with higher membrane localization of Kv7.4 and Kv7.5. In contrast, female rats in the proestrous and oestrous stages exhibited reduced sensitivity to ML213, associated with decreased Kv7.5 membrane abundance. In this group, ERα attenuated both the Kv7 functional response to ML213 and the membrane localization of Kv7.5, whereas GPER1 was associated with reducing the membrane abundance of the channel without affecting functionality. In diestrous and metestrous rat bladders, ERα was not active in baseline conditions. Instead, GPER1 induced a removal of Kv7.5 from the membrane, without exerting any effect on the Kv7 functional response to ML213. These findings highlight a complex interplay between sex hormones and ERs in bladder smooth muscle cells, offering insights into sex-specific differences in bladder function and potential therapeutic targets for bladder disorders.