GPER mediates the acute effect of estrogen on sodium currents
Estrogen regulates multiple physiological processes through its
receptors (ERα, ERβ, and GPER). GPER is reported to be the key receptor
mediating the rapid action of estrogen (Revankar et al., 2019). In the
cardiovascular system, estrogen via GPER confers protection (Menazza &
Murphy, 2016). In this study, estrogen treatment was carried out for 1
hour, and thus we speculated that its effects could be mediated by GPER.
Activation of GPER with G1 increased peak I Nasimilar to estrogen. Moreover, siRNA-driven silencing of GPER or
inhibition with G15 abolished the effects of estrogen. This shows that
GPER mediated the effect of estrogen on peak I Na.
Under stress challenge, G1 suppressed the increase inI NaL and peak I Na caused
by ISO consistent with the effect of estrogen. These effects were
eliminated by siRNA-driven silencing of GPER or inhibition with G15,
suggesting that GPER mediates the rapid effects of estrogen on sodium
currents under stress. Another interesting finding in this study is that
inhibition of GPER alone affected the recovery from inactivation of
sodium channel. This suggests that GPER could be structurally or
homologically similar to sodium channel, hence G15 may directly alter
the function of sodium channel. This speculation deserves further
clarification.
The present results show that various concentrations of estrogen
enhanced the peak I Na, whereas medium
concentration of estrogen, that is, physiological concentration,
effectively antagonized the functional changes of sodium channels caused
by stress through GPER. These findings underscore the importance of
estrogen and its receptor GPER on sodium channel function. We show that
they hold great promise as druggable targets for the treatment of
cardiovascular diseases related to sodium channel or stress.