Alternative splicing of the CaV1.2 calcium channel and its role in cardiovascular diseases.

The L-type calcium channel CaV1.2 serves as a core trigger for excitation-contraction and excitation-transcription coupling in cardiovascular cells. Its abnormalities are closely linked to multiple cardiovascular diseases, including hypertension, arrhythmias, and cardiac hypertrophy. Alternative splicing (AS) generates CaV1.2 channel isoforms with distinct electrophysiological properties and drug sensitivity, finely tuning channel functions. This review systematically summarizes AS regulation and pathological significance of CaV1.2 in the cardiovascular system. Three key splicing events, mutually exclusive exons 8/8a, cassette exon 9* and exon 33, impact channel gating, calcium influx, and drug responsiveness. These AS events are dynamically regulated by splicing factors such as Rbfox1/2, PTBP1, and RBM20. We further analyze aberrant CaV1.2 splicing in hypertension, heart failure, myocardial infarction, and diabetic cardiomyopathy. Finally, we discuss preclinical and clinical advances of antisense oligonucleotides for treating cardiovascular CaV1.2 channelopathies. This review aims to clarify the regulatory network of CaV1.2 AS, providing theoretical evidence for precision therapies based on splicing modulation.