Exclusion of alternative exon 33 of Ca1.2 calcium channels in heart is proarrhythmogenic.

Alternative splicing changes the Ca1.2 calcium channel electrophysiological property, but the in vivo significance of such altered channel function is lacking. Structure-function studies of heterologously expressed Ca1.2 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 Ca1.2 calcium channel in heart function. Exclusion of exon 33 in Ca1.2 channels has been reported to shift the activation potential -10.4 mV to the hyperpolarized direction, and increased expression of Ca1.2 channels was observed in rat myocardial infarcted hearts. However, how a change in Ca1.2 channel electrophysiological property, due to alternative splicing, might affect cardiac function in vivo is unknown. To address these questions, we generated m exon 33-null mice. These mice contained Ca1.2 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 Ca1.2 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 Ca1.2 channels may play in the pathogenesis of human heart failure remains unclear.