Publication details
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 | |
|---|---|
| Year of publication | 2026 |
| Type | Peer-reviewed scientific article |
| Magazine / Source | EUROPACE |
| MU Faculty or unit | |
| Citation | |
| web | https://academic.oup.com/europace/article/28/7/euag156/8711184 |
| Doi | https://doi.org/10.1093/europace/euag156 |
| Keywords | long QT; KCNQ1; Genetic variant; R562S; beta-adrenergic stimulation; I (Ks) |
| Description | Aims 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. Methods and results 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 corrected QT (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 I-Ks with a rightward shift of the voltage dependence of activation, and, importantly, a lack of responsiveness to beta-adrenergic stimulation. The latter seems to be related to a modified interaction of the modulatory KCNE1 subunit with Kv7.1. The pro-arrhythmic potential of R562S dysfunction, mediated by delayed afterdepolarizations during beta-adrenergic stimulation, could be effectively prevented by mild (5%) inhibition of L-type Ca2+ current (I-Ca). Conclusion R562S-Kv7.1 is the first variant in helix C causing an impaired response of I-Ks channel to beta-adrenergic stimulation, likely due to altered interactions between channel subunits, namely Kv7.1 and KCNE1. Mild I-Ca inhibition was suggested as a new treatment option. |
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