A benzodiazepine activator locks Kv7.1 channels open by electro-mechanical uncoupling

作者：Julian A. Schreiber, Melina Möller, Mark A. Zaydman, Lu Zhao, Zachary Beller, S. Becker, Nadine Ritter, Panpan Hou, Jingyi Shi, Jon Silva, Eva Wrobel, Nathalie Strutz‐Seebohm, Niels Decher, Nicole Schmitt, Sven G. Meuth, Martina Düfer, Bernhard Wünsch, Jianmin Cui, Guiscard Seebohm · 发表于：Communications Biology · 年份：2022 · DOI：10.1038/s42003-022-03229-8 · 被引用次数：17 · 研究领域：Cardiac electrophysiology and arrhythmias、Ion channel regulation and function、Neuroscience and Neural Engineering

Abstract Loss-of-function mutations in K v 7.1 often lead to long QT syndrome (LQTS), a cardiac repolarization disorder associated with arrhythmia and subsequent sudden cardiac death. The discovery of agonistic I Ks modulators may offer a new potential strategy in pharmacological treatment of this disorder. The benzodiazepine derivative ( R )-L3 potently activates K v 7.1 channels and shortens action potential duration, thus may represent a starting point for drug development. However, the molecular mechanisms underlying modulation by ( R )-L3 are still unknown. By combining alanine scanning mutagenesis, non-canonical amino acid incorporation, voltage-clamp electrophysiology and fluorometry, and in silico protein modelling, we show that ( R )-L3 not only stimulates currents by allosteric modulation of the pore domain but also alters the kinetics independently from the pore domain effects. We identify novel ( R )-L3-interacting key residues in the lower S4-segment of K v 7.1 and observed an uncoupling of the outer S4 segment with the inner S5, S6 and selectivity filter segments.