Understanding alternative splicing of Ca(v)1.2 calcium channels for a new approach towards individualized medicine

Calcium channel blockers (CCBs) are widely used to treat cardiovascular diseases such as hypertension, angina pectoris, hypertrophic cardiomyopathy, and supraventricular tachycardia. CCBs selectively inhibit the inward flow of calcium ions through voltage-gated calcium channels, particularly Ca(v)1.2, that are expressed in the cardiovascular system. Changes to the molecular structure of Ca(v)1.2 channels could affect sensitivity of the channels to blockade by CCBs. Recently, extensive alternative splicing was found in Ca(v)1.2 channels that generated wide phenotypic variations. Cardiac and smooth muscles express slightly different, but functionally important Ca(v)1.2 splice variants. Alternative splicing could also modulate the gating properties of the channels and giving rise to different responses to inhibition by CCBs. Importantly, alternative splicing of Ca(v)1.2 channels may play an important role to influence the outcome of many cardiovascular disorders. Therefore, the understanding of how alternative splicing impacts Ca(v)1.2 channels pharmacology in various diseases and different organs may provide the possibility for individualized therapy with minimal side effects.