The Departments of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester 55905, MN, USA; Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Rochester 55905, MN, USA.
The Departments of Cardiovascular Medicine, Mayo Clinic, 200 First Street SW, Rochester 55905, MN, USA.
Biochim Biophys Acta Mol Basis Dis. 2021 Dec 1;1867(12):166247. doi: 10.1016/j.bbadis.2021.166247. Epub 2021 Sep 4.
The Sorbin and SH3 domain-containing protein 2 (Sorbs2) is an important component of cardiomyocyte sarcomere. It has been recently reported that loss of Sorbs2 is causally associated with arrhythmogenic cardiomyopathy in human. However, the ionic mechanisms leading to cardiac arrhythmogenesis by Sorbs2 deficiency are unknown. In this study, we hypothesized that Sorbs2 plays an important role in regulating cardiac ion channel expression and function. Using electrophysiological and molecular biological approaches, we found that the Sorbs2 knockout (KO) mice progressively developed cardiac structural and electrical remodeling as early as 1 to 2 months of age and died prematurely at 5 to 7 months of age. Electrocardiographic recordings showed that Sorbs2 KO mice had conduction delays, spontaneous ventricular extrasystoles and polymorphic ventricular tachyarrhythmia. Intracellular recordings revealed abnormal action potentials with depolarized resting potential, reduced upstroke velocity, prolonged repolarization, and effective refractory period in the ventricular preparations of Sorbs2 KO mice. Patch clamp experiments demonstrated that Sorbs2 KO mice displayed distinct abnormalities in the expression and function of cardiac ion channels, including those of the voltage-gated Na channels, L-type Ca channels, the voltage-gated K channels and the inward-rectifier K channels. Moreover, Sorbs2 physically interacted with the RNAs and/or proteins of important cardiac ion channels and directly regulated their expression in vitro. Our results indicate that Sorbs2 plays a pivotal role in the regulation of cardiac channel physiology. Loss of Sorbs2 promotes cardiac ion channelopathies and life-threatening arrhythmias.
Sorbin 和 SH3 结构域蛋白 2（Sorbs2）是心肌细胞肌节的重要组成部分。最近有报道称，Sorbs2 的缺失与人的心律失常性心肌病有因果关系。然而，Sorbs2 缺乏导致心脏心律失常发生的离子机制尚不清楚。在这项研究中，我们假设 Sorbs2 在调节心脏离子通道表达和功能方面发挥着重要作用。我们使用电生理学和分子生物学方法发现，Sorbs2 敲除（KO）小鼠早在 1 至 2 个月龄时就逐渐出现心脏结构和电重构，并在 5 至 7 个月龄时过早死亡。心电图记录显示 Sorbs2 KO 小鼠存在传导延迟、自发性室性期外收缩和多形性室性心动过速。细胞内记录显示 Sorbs2 KO 小鼠的心室标本中动作电位异常，静息电位去极化，上升速度减慢，复极化延长，有效不应期缩短。膜片钳实验表明，Sorbs2 KO 小鼠心脏离子通道的表达和功能存在明显异常，包括电压门控 Na 通道、L 型 Ca 通道、电压门控 K 通道和内向整流 K 通道。此外，Sorbs2 与重要心脏离子通道的 RNA 和/或蛋白发生物理相互作用，并在体外直接调节其表达。我们的结果表明，Sorbs2 在调节心脏通道生理学方面起着关键作用。Sorbs2 的缺失促进了心脏离子通道病和危及生命的心律失常。
