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Kir2.1 dysfunction at the sarcolemma and the sarcoplasmic reticulum causes arrhythmias in a mouse model of Andersen-Tawil syndrome type 1.

Authors :
Macías Á
González-Guerra A
Moreno-Manuel AI
Cruz FM
Gutiérrez LK
García-Quintáns N
Roche-Molina M
Bermúdez-Jiménez F
Andrés V
Vera-Pedrosa ML
Martínez-Carrascoso I
Bernal JA
Jalife J
Source :
Nature cardiovascular research [Nat Cardiovasc Res] 2022 Oct; Vol. 1 (10), pp. 900-917. Date of Electronic Publication: 2022 Oct 17.
Publication Year :
2022

Abstract

Andersen-Tawil syndrome type 1 (ATS1) is associated with life-threatening arrhythmias of unknown mechanism. In this study, we generated and characterized a mouse model of ATS1 carrying the trafficking-deficient mutant Kir2.1 <superscript>Δ314-315</superscript> channel. The mutant mouse recapitulates the electrophysiological phenotype of ATS1, with QT prolongation exacerbated by flecainide or isoproterenol, drug-induced QRS prolongation, increased vulnerability to reentrant arrhythmias and multifocal discharges resembling catecholaminergic polymorphic ventricular tachycardia (CPVT). Kir2.1 <superscript>Δ314-315</superscript> cardiomyocytes display significantly reduced inward rectifier K <superscript>+</superscript> and Na <superscript>+</superscript> currents, depolarized resting membrane potential and prolonged action potentials. We show that, in wild-type mouse cardiomyocytes and skeletal muscle cells, Kir2.1 channels localize to sarcoplasmic reticulum (SR) microdomains, contributing to intracellular Ca <superscript>2+</superscript> homeostasis. Kir2.1 <superscript>Δ314-315</superscript> cardiomyocytes exhibit defective SR Kir2.1 localization and function, as intact and permeabilized Kir2.1 <superscript>Δ314-315</superscript> cardiomyocytes display abnormal spontaneous Ca <superscript>2+</superscript> release events. Overall, defective Kir2.1 channel function at the sarcolemma and the SR explain the life-threatening arrhythmias in ATS1 and its overlap with CPVT.<br /> (© 2022. The Author(s).)

Details

Language :
English
ISSN :
2731-0590
Volume :
1
Issue :
10
Database :
MEDLINE
Journal :
Nature cardiovascular research
Publication Type :
Academic Journal
Accession number :
39195979
Full Text :
https://doi.org/10.1038/s44161-022-00145-2