Hexachlorophene Is a Potent KCNQ1/KCNE1 Potassium Channel Activator Which Rescues LQTs Mutants

Zheng, Yueming; Zhu, Xuejing; Zhou, Pingzheng; Lan, Xi; Xu, Haiyan; Li, Min; Gao, Zhaobing

The homomeric KCNQ1 mediates a characteristic outward current with detectable inactivation (Fig. 3A) . In the presence of 10 mM HCP, steady-state outward currents at different depolarizing voltages were greatly potentiated. The potentiation on the KCNQ1 channel mediated by previous reported KCNQ1 activators, such as ZnPy and R-L3, involves a hyperpolarizing shift of V 1/2 . To determine the HCP effects on the homomeric KCNQ1, we examined the G-V curves of the KCNQ1 in the absence and presence of 10 mM HCP. Before application of HCP, the V 1/2 value was 219.4361.39 mV (Fig. 3E) . After application of HCP, the V 1/2 value was shifted to 249.3561.93 mV with a left-shifting around 30 mV. Inactivation is a distinctive feature for KCNQ1. The inhibition of inactivation by activators, such as ZnPy, is thought to be a contributing factor for an overall increase Novel KCNQ1/KCNE1 Activator Hexachlorophene PLOS ONE | www.plosone.org of current amplitude [13] . We analyzed the inactivation kinetics at different depolarization steps and found no detectable difference before and after application of HCP (Fig. 3B) . Hence, HCP increases overall conductance of the KCNQ1 by left-shifting the G-V curve but not affecting inactivation. In addition, HCP also induced delaying of deactivation in hyperpolarizing voltages (Fig. 3C) . In the presence of 10 mM HCP, time constant of deactivation was slowed from 40.0567.52 ms to 265.51623.23 ms (n = 3, p,0.01). The reduction of deactivation rate is consistent with the overall increase of current amplitude or G max .