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 α 1 pore-forming subunit and the accessory subunits Ca v β, Ca v α 2 δ, and Ca v γ. Ca v β 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 β silencing, we demonstrate that Ca v β 2 downregulation enhances α1-adrenergic receptor agonist-induced cardiomyocyte hypertrophy. We report that a pool of Ca v β 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 β 2 in cardiomyocytes inhibits in vitro -induced hypertrophy. Quantitative proteomic analyses showed that Ca v β 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 β 2 -downregulated cardiomyocytes had a 2-fold increase in calpain activity as compared to control cells. Furthermore, inhibition of calpain activity in Ca v β 2 -downregulated cells abolished the enhanced α1-adrenergic receptor agonist-induced hypertrophy observed in these cells. Our findings indicate that in cardiomyocytes, a nuclear pool of Ca v β 2 participates in cellular functions that are independent of LTCC activity. They also indicate that a downregulation of nuclear Ca v β 2 during cardiomyocyte hypertrophy promotes the activation of calpain-dependent hypertrophic pathways.