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

6 Scopus citations


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
Issue number1
StatePublished - Dec 2022


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