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在1型安德森-塔维尔综合征小鼠模型中，肌膜和肌浆网上的Kir2.1功能障碍会导致心律失常。

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

作者信息

Macías Álvaro, González-Guerra Andrés, Moreno-Manuel Ana I, Cruz Francisco M, Gutiérrez Lilian K, García-Quintáns Nieves, Roche-Molina Marta, Bermúdez-Jiménez Francisco, Andrés Vicente, Vera-Pedrosa María Linarejos, Martínez-Carrascoso Isabel, Bernal Juan A, Jalife José

机构信息

Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.

CIBER de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.

出版信息

Nat Cardiovasc Res. 2022 Oct;1(10):900-917. doi: 10.1038/s44161-022-00145-2. Epub 2022 Oct 17.

DOI:10.1038/s44161-022-00145-2
PMID:39195979
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11358039/
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 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 cardiomyocytes display significantly reduced inward rectifier K and Na 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 homeostasis. Kir2.1 cardiomyocytes exhibit defective SR Kir2.1 localization and function, as intact and permeabilized Kir2.1 cardiomyocytes display abnormal spontaneous Ca 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.

摘要

1型安德森-陶威尔综合征（ATS1）与机制不明的危及生命的心律失常有关。在本研究中，我们构建并鉴定了携带转运缺陷型突变体Kir2.1通道的ATS1小鼠模型。该突变小鼠重现了ATS1的电生理表型，氟卡尼或异丙肾上腺素可加剧QT延长、药物诱导的QRS延长、折返性心律失常易感性增加以及类似于儿茶酚胺能多形性室性心动过速（CPVT）的多灶性放电。Kir2.1心肌细胞表现出内向整流钾电流和钠电流显著降低、静息膜电位去极化以及动作电位延长。我们发现，在野生型小鼠心肌细胞和骨骼肌细胞中，Kir2.1通道定位于肌浆网（SR）微区，有助于细胞内钙稳态。Kir2.1心肌细胞表现出SR中Kir2.1定位和功能缺陷，因为完整和通透的Kir2.1心肌细胞显示出自发性钙释放异常事件。总体而言，肌膜和SR处的Kir2.1通道功能缺陷解释了ATS1中危及生命的心律失常及其与CPVT的重叠。

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