Aberrant Splicing Promotes Proteasomal Degradation of L-type CaV1.2 Calcium Channels by Competitive Binding for CaVβ Subunits in Cardiac Hypertrophy

Decreased expression and activity of Ca(V)1.2 calcium channels has been reported in pressure overload-induced cardiac hypertrophy and heart failure. However, the underlying mechanisms remain unknown. Here we identified in rodents a splice variant of Ca(V)1.2 channel, named Ca(V)1.2(e21+22r) that contained the pair of mutually exclusive exons 21 and 22. This variant was highly expressed in neonatal hearts. The abundance of this variant was gradually increased by 12.5-folds within 14 days of transverse aortic banding that induced cardiac hypertrophy in adult mouse hearts and was also elevated in left ventricles from patients with dilated cardiomyopathy. Although this variant did not conduct Ca2+ ions, it reduced the cell-surface expression of wild-type Ca(V)1.2 channels and consequently decreased the whole-cell Ca2+ influx via the Ca(V)1.2 channels. In addition, the Ca(V)1.2(e21+22) variant interacted with Ca-V beta subunits significantly more than wild-type Ca(V)1.2 channels, and competition of Ca-V beta subunits by Ca(V)1.2(e21+22) consequently enhanced ubiquitination and subsequent proteasomal degradation of the wild-type Ca(V)1.2 channels. Our findings show that the resurgence of a specific neonatal splice variant of Ca(V)1.2 channels in adult heart under stress may contribute to heart failure.