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

Julian A. Schreiber, Melina Möller, Mark Zaydman, Lu Zhao, Zachary Beller, Sebastian 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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Loss-of-function mutations in Kv7.1 often lead to long QT syndrome (LQTS), a cardiac repolarization disorder associated with arrhythmia and subsequent sudden cardiac death. The discovery of agonistic IKs modulators may offer a new potential strategy in pharmacological treatment of this disorder. The benzodiazepine derivative (R)-L3 potently activates Kv7.1 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 Kv7.1 and observed an uncoupling of the outer S4 segment with the inner S5, S6 and selectivity filter segments.

Original languageEnglish
Article number301
JournalCommunications Biology
Volume5
Issue number1
DOIs
StatePublished - Dec 2022

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