Aberrant Splicing Promotes Proteasomal Degradation of L-type Ca_V1.2 Calcium Channels by Competitive Binding for Ca_V? Subunits in Cardiac Hypertrophy.

ABSTRACT: Decreased expression and activity of Ca_V1.2 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_V1.2 channel, named Ca_V1.2_e21+22, 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_V1.2 channels and consequently decreased the whole-cell Ca²⁺ influx via the Ca_V1.2 channels. In addition, the Ca_V1.2_e21+22 variant interacted with Ca_V? subunits significantly more than wild-type Ca_V1.2 channels, and competition of Ca_V? subunits by Ca_V1.2_e21+22 consequently enhanced ubiquitination and subsequent proteasomal degradation of the wild-type Ca_V1.2 channels. Our findings show that the resurgence of a specific neonatal splice variant of Ca_V1.2 channels in adult heart under stress may contribute to heart failure.

SUBMITTER: Hu Z 

PROVIDER: S-EPMC5059693 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature