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

Current therapy for LQTs is inadequate. Because the critical role of the current mediated by KCNQ1/KCNE1 in repolarization of cardiac action potential, augmenting KCNQ1/KCNE1 by small molecule may represent an attractive strategy to treat LQTs. Our study found that 1 mM HCP effectively potentiated native IKs and left-shifted the G-V curve. IKs was activated instantaneously in higher concentrations of HCP, including 3 mM or 10 mM. The effects of HCP on shortening the action potential duration in cardiomyocytes further supports its potential use for development therapeutics for LQTs either as a tool compound or as a lead compound. The slight reduction of the action potential amplitude suggests that HCP may affect other channel(s). Most of LQTs- causing mutations were from KCNQ1 among the identified LQTassociated genes including KCNQ1, HERG,SCN5A, KCNE1 and KCNE2 [4, 5, 19] . These mutations cause reduction in the potassium current, thereby leading to prolongation of cardiac repolarization [7, 28, 29] . Many mutations of LQTs are trafficked to the plasma membrane, suggesting no major folding defects, but reduction of activity [7, 29] . Among the tested mutants, R190Q is a novel identified mutation located at the linker of S2-S3. It is thought to affect the activation gating of KCNQ1/KCNE1. R587M is a trafficking deficient mutation located at the Cterminal end. Loss of function of R190Q and R587M is consistent to previous reports [30, 31] . R243C is a missense mutation located in S4, a transmembrane segment implicated in activation gating of potassium channels [20] . The suppressed current of R243C/ KCNE1 is consistent with the notion that the mutation prevents normal channel gating. The additional mutant R539W was identified in patients with a dominantly inherited classical long QT (Romano-Ward) syndrome. R539 is located at the C-terminal tail and shows a reduced PIP2 binding affinity [21] . It has been demonstrated that PIP2 is necessary for the function of various ion channels including KCNQ channels [32, 33] . A recent study showed that the PIP2 affinity of R539W/KCNE1 is reduced [34] . Potentiation of both R243C and R539W suggests HCP is capable of restoring loss-of-function caused by various mutations, either with impaired gating (R243C) or reduced PIP2 affinity (R539W). However, the effects of HCP on the KCNQ1/KCNE1 mutant channels are weaker than that on wild type KCNQ1/KCNE1 channel. For the wild type KCNQ1/KCNE1 channel, 10 mM HCP dramatically left shifts the G-V curve around 266.0566.15 mV. In contrast, the left shifting for KCNQ1(R539W)/KCNE1 is only 229.3562.74 mV, and furthermore, in the case of KCNQ1(R243C)/KCNE1, the shifting was negligible. Considering physiological efficiency of an activator of KCNQ channel more relies on its effect on the G-V relationship, the weaker or loss of effects of HCP on the G-V curves of these KCNQ1/KCNE1 mutant channels should be considered as major factors in developing therapeutic for LQTs.