期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 114, 期 21, 页码 E4288-E4295出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1617205114
关键词
CaV1.2 channel; alternative splicing; cardiac function; cardiac arrhythmia; heart failure
资金
- Biomedical Research Council
- National Medical Research Council of Singapore
Alternative splicing changes the Ca(V)1.2 calcium channel electrophysiological property, but the in vivo significance of such altered channel function is lacking. Structure-function studies of heterologously expressed Ca(V)1.2 channels could not recapitulate channel function in the native milieu of the cardiomyocyte. To address this gap in knowledge, we investigated the role of alternative exon 33 of the Ca(V)1.2 calcium channel in heart function. Exclusion of exon 33 in Ca(V)1.2 channels has been reported to shift the activation potential -10.4 mV to the hyperpolarized direction, and increased expression of Ca(V)1.2.33 channels was observed in rat myocardial infarcted hearts. However, how a change in Ca(V)1.2 channel electrophysiological property, due to alternative splicing, might affect cardiac function in vivo is unknown. To address these questions, we generated mCacna1c exon 33(-/-)-null mice. These mice contained Ca(V)1.2.33 channels with a gain-of-function that included conduction of larger currents that reflects a shift in voltage dependence and a modest increase in single-channel open probability. This altered channel property underscored the development of ventricular arrhythmia, which is reflected in significantly more deaths of exon 33-/-mice from beta-adrenergic stimulation. In vivo telemetric recordings also confirmed increased frequencies in premature ventricular contractions, tachycardia, and lengthened QT interval. Taken together, the significant decrease or absence of exon 33-containing Ca(V)1.2 channels is potentially proarrhythmic in the heart. Of clinical relevance, human ischemic and dilated cardiomyopathy hearts showed increased inclusion of exon 33. However, the possible role that inclusion of exon 33 in Ca(V)1.2 channels may play in the pathogenesis of human heart failure remains unclear.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据