1. Exclusion of alternative exon 33 of CaV1.2 calcium channels in heart is proarrhythmogenic.
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Guang Li, Juejin Wang, Ping Liao, Bartels, Peter, Hengyu Zhang, Dejie Yu, Mui Cheng Liang, Kian Keong Poh, Chye Yun Yu, Fengli Jiang, Tan Fong Yong, Yuk Peng Wong, Zhenyu Hu, Hua Huang, Guangqin Zhang, Galupo, Mary Joyce, Jin-Song Bian, Ponniah, Sathivel, Trasti, Scott Lee, and See, Kelvin
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CALCIUM channels ,HEART cells ,EXONS (Genetics) ,MYOCARDIAL infarction ,ARRHYTHMIA ,PHYSIOLOGY ,GENETICS ,DISEASE risk factors - Abstract
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 CaV 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 CaV 1.2 calcium channel in heart function. Exclusion of exon 33 in CaV 1.2 channels has been reported to shift the activation potential -10.4 mV to the hyperpolarized direction, and increased expression of CaV 1.2Δ33 channels was observed in rat myocardial infarcted hearts. However, how a change in CaV 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 CaV 1.2Δ33 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 CaV 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 CaV 1.2 channels may play in the pathogenesis of human heart failure remains unclear. [ABSTRACT FROM AUTHOR]- Published
- 2017
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