Abstract
Decreased expression and activity of CaV1.2 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 CaV1.2 channel, named CaV1.2e21+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 CaV1.2 channels and consequently decreased the whole-cell Ca2+ influx via the CaV1.2 channels. In addition, the CaV1.2e21+22 variant interacted with CaVβ subunits significantly more than wild-type CaV1.2 channels, and competition of CaVβ subunits by CaV1.2e21+22 consequently enhanced ubiquitination and subsequent proteasomal degradation of the wild-type CaV1.2 channels. Our findings show that the resurgence of a specific neonatal splice variant of CaV1.2 channels in adult heart under stress may contribute to heart failure.
Highlights
The expression of CaV1.2e21+22 diminishes during postnatal cardiac maturation and re-emerges in pressure-overload induced cardiac hypertrophy. This fetal-like alternative splicing pattern of CaV1.2 channels in the hypertrophied heart is in agreement with a recent report that alternative splicing events in response to transverse aortic constriction (TAC) displayed reciprocal expression changes during postnatal cardiac development versus heart failure[22]
Mutations in CaV1.2 channels are associated with multiple heart diseases including Timothy syndrome that is characterized by a long QT interval and ventricular arrhythmia due to sustained activation of CaV1.2 channels[23,24] and Brugada syndrome that is notable for a short QT interval and sudden cardiac death due to inactivation of CaV1.2 channels[25]
The disparities might be attributed to activation of calcineurin activation or neurohumoral effects[8]. It might be partly explained by the existence of two distinct subsets of the channels[24,29,30]: One subset assembled in the T-tubules for calcium-induced calcium release with ryanodine receptors for excitation-contraction coupling[31,32], and the other subset (~50% in mice)[33] enriched in caveolae to activate the transcription factor NFAT for cardiac hypertrophy
Summary
In human failing cardiomyocytes the density of CaV1.2 channels was decreased compared to normal cardiomyocytes[12] In line with these findings, decreased CaV1.2 channel activity was recently reported to induce cardiac hypertrophy and heart failure www.nature.com/scientificreports/. The hypertrophied cardiomyocytes induced by pressure overload showed drastic decrease in CaV1.2 channel density and activity due to reduced expression of the CaV1.2 channels. The pore-forming α1 subunit undergoes extensive alternative splicing that potentially generates multiple functionally diversified CaV1.2 variants in human[13] and rodent hearts[14]. As the newly identified channel variant does not conduct Ca2+ ions, we hypothesized that it may account for the reduced expression and activity of CaV1.2 channels in hypertrophied cardiomyocytes induced by pressure overload[14]
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