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

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

doi:10.1371/journal.pone.0051820

Abstract

The voltage-gated KCNQ1 potassium channel is expressed in cardiac tissues, and coassembly of KCNQ1 with an auxiliary KCNE1 subunit mediates a slowly activating current that accelerates the repolarization of action potential in cardiomyocytes. Mutations of KCNQ1 genes that result in reduction or loss of channel activity cause prolongation of repolarization during action potential, thereby causing long QT syndrome (LQTs). Small molecule activators of KCNQ1/KCNE1 are useful both for understanding the mechanism of the complex activity and for developing therapeutics for LQTs. In this study we report that hexachlorophene (HCP), the active component of the topical anti-infective prescription drug pHisoHex, is a KCNQ1/KCNE1 activator. HCP potently increases the current amplitude of KCNQ1/KCNE1 expressed by stabilizing the channel in an open state with an EC50 of 4.61±1.29 μM. Further studies in cardiomyocytes showed that HCP significantly shortens the action potential duration at 1 μM. In addition, HCP is capable of rescuing the loss of function of the LQTs mutants caused by either impaired activation gating or phosphatidylinositol-4,5-bisphosphate (PIP2) binding affinity. Our results indicate HCP is a novel KCNQ1/KCNE1 activator and may be a useful tool compound for the development of LQTs therapeutics.

Highlights

KCNQ1 is the pore forming subunit, tetrameric KCNQ1 complexes give rise to functional channels. In native cells such as cardiomyocytes, KCNQ1 coassembles with a non-conductive accessory KCNE1 subunit, a small single transmembrane protein encoded by KCNE1 gene
Our study indicates that HCP as an effective KCNQ1/KCNE1 activator
To obtain a better understanding for HCP activity on KCNQ channels, we examined its effects on KCNQ1, KCNQ1/KCNE1, KCNQ2, KCNQ3, KCNQ2/3 and KCNQ4 isoforms by electrophysiology

Summary

Introduction

KCNQ (or Kv7) channels are voltage-gated potassium channels. They mediate sub-threshold, noninactivating voltage-gated potassium currents that have important roles in controlling membrane excitability [1]. Of the five known isoforms, KCNQ1–5, KCNQ1 is the only one predominantly expressed in heart. KCNQ1 is the pore forming subunit, tetrameric KCNQ1 complexes give rise to functional channels. In native cells such as cardiomyocytes, KCNQ1 coassembles with a non-conductive accessory KCNE1 subunit, a small single transmembrane protein encoded by KCNE1 gene. The heteromultimeric KCNQ1/ KCNE1 was proposed to mediate a slowly activating current that accelerates the repolarization of action potential in cardiac tissues, known as IKs [2,3]

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