Exclusion of alternative exon 33 of Ca V 1.2 calcium channels in heart is proarrhythmogenic

Significance To directly address in vivo significance of the altered Ca V 1.2 channel property arising from alternative splicing, we generated Ca V 1.2 exon 33-specific knockout (exon 33 −/− ) mice. Here, we showed that the exclusion of alternative exon 33 altered Ca V 1.2 biophysical property, leading to greater I Ca density. This increase in current density induced prolongation of ventricular cardiomyocyte action potential duration, and the cardiomyocytes exhibited increased early afterdepolarizations and autonomous action potentials—hallmarks of arrhythmias. In vivo, exon 33 −/− mice had increased occurrences of premature ventricular contractions, tachycardia, and lengthened QT interval. As such, exclusion of exon 33 of the Ca V 1.2 channel is proarrhythmogenic. Although failing human hearts had greater inclusion of exon 33, it is unclear whether the inclusion is compensatory, neutral, or damaging.