C-terminal long-QT type 1 R562S-Kv7.1 variant, the first variant in helix C impairing β-adrenergic response of the slow delayed rectifier K+ channel.

Authors

Martin Král, Olga Švecová, Roman Kula, Nina Kadášová, Jindřich Lněnička, Iva Synková, Dominika Traj, Larisa Chmelikova, Michal Pásek, Jan Hošek, Katarzyna Anna Radasczkiewicz, Irena Andršová, Pavel Vít, Karel Berka, Tomáš Novotný, Markéta Bébarová

Published in

Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. Jun 18, 2026. Epub Jun 18, 2026.

Abstract

Kv7.1 variants, associated with long-QT syndrome type 1 (LQT1) and altering the function of the slow delayed rectifier K+ (IKs) channel, may result in arrhythmias, especially during exercise. This study focused on complex analysis of the R562S-Kv7.1 variant located in helix C of the Kv7.1 C-terminus, which was identified in four putatively unrelated families in the Czech Republic.
The clinical and genetic investigation was followed by functional analysis (whole-cell patch clamp, confocal microscopy, computational simulations) and structural modelling.
The genetic analysis suggested that R562S-Kv7.1 might be a founder LQT1 variant in Central Europe. R562S carriers showed a significantly prolonged QTc interval at rest and a significantly higher QTc prolongation after exercise vs. healthy relatives. The functional analysis of R562S channels demonstrated their preserved membrane localization, a significant decrease in IKs with a rightward shift of the voltage dependence of activation, and, importantly, a lack of responsiveness to β-adrenergic stimulation. The latter seems to be related to a modified interaction of the modulatory KCNE1 subunit with Kv7.1. The proarrhythmic potential of R562S dysfunction, mediated by delayed afterdepolarizations during β-adrenergic stimulation, could be effectively prevented by mild (5%) inhibition of L-type Ca2+ current (ICa).
R562S-Kv7.1 is the first variant in helix C causing an impaired response of IKs channel to β-adrenergic stimulation, likely due to altered interactions between channel subunits, namely Kv7.1 and KCNE1. Mild ICa inhibition was suggested as a new treatment option.

PMID:
42314170
Bibliographic data and abstract were imported from PubMed on 19 Jun 2026.

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