title: Hexachlorophene is a potent KCNQ1/KCNE1 potassium channel activator which rescues LQTs mutants.
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 EC(50) 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.
authors.affiliation: Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yueming
authors.initials: Y
authors.lastname: Zheng
authors.forename: Xuejing
authors.initials: X
authors.lastname: Zhu
authors.forename: Pingzheng
authors.initials: P
authors.lastname: Zhou
authors.forename: Xi
authors.initials: X
authors.lastname: Lan
authors.forename: Haiyan
authors.initials: H
authors.lastname: Xu
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Zhaobing
authors.initials: Z
authors.lastname: Gao
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006582:Hexachlorophene / Q000494:pharmacology*; D051657:KCNQ1 Potassium Channel / Q000235:genetics / Q000378:metabolism*; D008133:Long QT Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000494:pharmacology
chemical_list: D051657:KCNQ1 Potassium Channel; D019269:Phosphatidylinositol 4,5-Diphosphate; D006582:Hexachlorophene