Exclusion of alternative exon 33 of Ca

To directly address in vivo significance of the altered CaV1.2 channel property arising from alternative splicing, we generated CaV1.2 exon 33-specific knockout (exon 33−/−) mice. Here, we showed that the exclusion of alternative exon 33 altered CaV1.2 biophysical property, leading to greater ICa 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 CaV1.2 channel is proarrhythmogenic. Although failing human hearts had greater inclusion of exon 33, it is unclear whether the inclusion is compensatory, neutral, or damaging.