The β(2)-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.