AUTHOR=Pickel Simone , Cruz-Garcia Yiliam , Bandleon Sandra , Barkovits Katalin , Heindl Cornelia , Völker Katharina , Abeßer Marco , Pfeiffer Kathy , Schaaf Alice , Marcus Katrin , Eder-Negrin Petra , Kuhn Michaela , Miranda-Laferte Erick 

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

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=8

YEAR=2021

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2021.704657

DOI=10.3389/fcvm.2021.704657

ISSN=2297-055X

ABSTRACT=<p>L-type voltage-gated calcium channels (LTCCs) regulate crucial physiological processes in the heart. They are composed of the Ca<sub>v</sub>α<sub>1</sub> pore-forming subunit and the accessory subunits Ca<sub>v</sub>β, Ca<sub>v</sub>α<sub>2</sub>δ, and Ca<sub>v</sub>γ. Ca<sub>v</sub>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<sub>v</sub>β silencing, we demonstrate that Ca<sub>v</sub>β<sub>2</sub> downregulation enhances α1-adrenergic receptor agonist-induced cardiomyocyte hypertrophy. We report that a pool of Ca<sub>v</sub>β<sub>2</sub> is targeted to the nucleus in cardiomyocytes and that the expression of this nuclear fraction decreases during <italic>in vitro</italic> and <italic>in vivo</italic> induction of cardiac hypertrophy. Moreover, the overexpression of nucleus-targeted Ca<sub>v</sub>β<sub>2</sub> in cardiomyocytes inhibits <italic>in vitro</italic>-induced hypertrophy. Quantitative proteomic analyses showed that Ca<sub>v</sub>β<sub>2</sub> 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<sub>v</sub>β<sub>2</sub>-downregulated cardiomyocytes had a 2-fold increase in calpain activity as compared to control cells. Furthermore, inhibition of calpain activity in Ca<sub>v</sub>β<sub>2</sub>-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<sub>v</sub>β<sub>2</sub> participates in cellular functions that are independent of LTCC activity. They also indicate that a downregulation of nuclear Ca<sub>v</sub>β<sub>2</sub> during cardiomyocyte hypertrophy promotes the activation of calpain-dependent hypertrophic pathways.</p>