The β2-Subunit of Voltage-Gated Calcium Channels Regulates Cardiomyocyte Hypertrophy

L-type voltage-gated calcium channels (LTCCs) regulate crucial physiological processes in the heart. They are composed of the Ca-v alpha(1) pore-forming subunit and the accessory subunits Ca-v beta, Ca-v alpha(2)delta, and Ca-v gamma. Ca-v beta is a cytosolic protein that regulates channel trafficking and activity, but it also exerts other LTCC-independent functions. Cardiac hypertrophy, a relevant risk factor for the development of congestive heart failure, depends on the activation of calcium-dependent pro-hypertrophic signaling cascades. Here, by using shRNA-mediated Ca-v beta silencing, we demonstrate that Ca-v beta(2) downregulation enhances alpha 1-adrenergic receptor agonist-induced cardiomyocyte hypertrophy. We report that a pool of Ca-v beta(2) is targeted to the nucleus in cardiomyocytes and that the expression of this nuclear fraction decreases during in vitro and in vivo induction of cardiac hypertrophy. Moreover, the overexpression of nucleus-targeted Ca-v beta(2) in cardiomyocytes inhibits in vitro-induced hypertrophy. Quantitative proteomic analyses showed that Ca-v beta(2) knockdown leads to changes in the expression of diverse myocyte proteins, including reduction of calpastatin, an endogenous inhibitor of the calcium-dependent protease calpain. Accordingly, Ca-v beta(2)-downregulated cardiomyocytes had a 2-fold increase in calpain activity as compared to control cells. Furthermore, inhibition of calpain activity in Ca-v beta(2)-downregulated cells abolished the enhanced alpha 1-adrenergic receptor agonist-induced hypertrophy observed in these cells. Our findings indicate that in cardiomyocytes, a nuclear pool of Ca-v beta(2) participates in cellular functions that are independent of LTCC activity. They also indicate that a downregulation of nuclear Ca-v beta(2) during cardiomyocyte hypertrophy promotes the activation of calpain-dependent hypertrophic pathways.