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

HCP represents a novel class of KCNQ1/KCNE1 activator R-L3 potentiates the homomeric KCNQ1 channel at very low concentration, but does not affect the KCNQ1/KCNE1 complex. Interestingly, potentiation effects of R-L3 on the complex seems dependent on the KCNE1 to KCNQ1 ratio. An increased ratio causes noticeable reduction of R-L3 activity [14] . Alanine scanning revealed that R-L3 may interact with specific residues located in the S5 or S6 transmembrane domains of KCNQ1 subunits [25] . Consistently, our previous study showed that residues critical for the potentiation effects by KCNE1 are clustered together in the S6 region in proximity with the critical residues for ZnPy [13] . Different from R-L3 and ZnPy, HCP potentiates both the homomeric KCNQ1 and the KCNQ1/ KCNE1 complex. Mefenamic acid, DIDS and PBA were reported KCNQ1/KCNE1 activators [15, 16] . Although all three compounds exhibit potent effects on the KCNQ1/KCNE1 complex, similar to HCP, the phenotypes of the three activators easily differentiate HCP from them. Mefenamic acid or DIDS also cause instantaneous opening of the KCNQ1/KCNE1 complex [26] . However, mefenamic acid and DIDS effects on the homomeric KCNQ1 are much weaker than HCP. They left-shift the G-V curve and slow deactivation but do not increase overall conductance of homomeric KCNQ1 [15, 27] . Differently, HCP significantly increases the overall conductance of the homomeric KCNQ1 (Fig. 2) . PBA potentiates both the KNCQ1 and the KCNQ1/KCNE1. Of interest, PBA exhibits inhibitory effect initially and then gradually potentiation effect on both homomeric KCNQ1 and the KCNQ1/KCNE1 complex. These again argue that PBA and HCP act via different mechanisms [16] . It is of interest that both PBA and HCP have slow off rate; the effects once reaching steady state were difficult to wash off. Taken together, these results suggest that HCP may represent a novel class of KCNQ1/KCNE1 activator.