文章基本信息

标题：Exclusion of alternative exon 33 of CaV1.2 calcium channels in heart is proarrhythmogenic
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作者：Guang Li ; Juejin Wang ; Ping Liao 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2017
卷号：114
期号：21
页码：E4288-E4295
DOI：10.1073/pnas.1617205114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Alternative splicing changes the Ca_V1.2 calcium channel electrophysiological property, but the in vivo significance of such altered channel function is lacking. Structure–function studies of heterologously expressed Ca_V1.2 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_V1.2 calcium channel in heart function. Exclusion of exon 33 in Ca_V1.2 channels has been reported to shift the activation potential −10.4 mV to the hyperpolarized direction, and increased expression of Ca_V1.2_Δ33 channels was observed in rat myocardial infarcted hearts. However, how a change in Ca_V1.2 channel electrophysiological property, due to alternative splicing, might affect cardiac function in vivo is unknown. To address these questions, we generated m Cacna1c exon 33^−/−-null mice. These mice contained Ca_V1.2_Δ33 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 β-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_V1.2 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_V1.2 channels may play in the pathogenesis of human heart failure remains unclear.
关键词：CaV1.2 channel ; alternative splicing ; cardiac function ; cardiac arrhythmia ; heart failure