Inhibitory effect of oestradiol on the cardiac KV7.1/KCNE1 channel is species dependent.

Abstract

Oestradiol (17β-E2) is reported to prolong the cardiac action potential duration and QT interval, in part by affecting cardiac ion channels. Previous studies found inhibiting 17β-E2 effects on the repolarizating cardiac K_V7.1/KCNE1 channel, or its native current, in heterologous expression systems or tissue from animal species. However, there is variability in reported 17β-E2 effects and required concentrations. In this work, we aimed to test whether a contributing factor may be different pharmacological profiles of K_V7.1/KCNE1 channels from different species. To this end, we used the two-electrode voltage clamp technique to characterize and quantitatively compare the effects of 17β-E2 on K_V7.1/KCNE1 channels from guinea pig, zebrafish, and rabbit expressed in Xenopus oocytes. We found that K_V7.1/KCNE1 of all tested species is inhibited by 17β-E2, although with species variability in the response. The guinea pig channel responded similar to previous reports for the human channel with a concentration-dependent reduction in the overall conductance. In contrast, the rabbit channel was sensitive to lower 17β-E2 concentrations, whereas the zebrafish channel responded with an additional inhibiting effect seen as a shifted voltage dependence of channel opening toward more positive voltages. By testing the 17β-E2 response of K_V7.1 alone, and by combining K_V7.1 and KCNE1 subunits from different species, we conclude that the species variability is not simply dictated by one of the subunits but rather by the K_V7.1/KCNE1 complex. The species variability in the 17β-E2 response of K_V7.1/KCNE1 could be considered when choosing appropriate animal models or interpreting findings from different experimental models.