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The β2-Subunit of Voltage-Gated Calcium Channels Regulates Cardiomyocyte Hypertrophy
Ist Teil von
Frontiers in cardiovascular medicine, 2021-07, Vol.8, p.704657-704657
Ort / Verlag
Frontiers Media S.A
Erscheinungsjahr
2021
Quelle
EZB Electronic Journals Library
Beschreibungen/Notizen
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.