{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T09:10:51Z","timestamp":1790759451163,"version":"4.1.0"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,7,7]],"date-time":"2021-07-07T00:00:00Z","timestamp":1625616000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:p>L-type voltage-gated calcium channels (LTCCs) regulate crucial physiological processes in the heart. They are composed of the Ca<jats:sub>v<\/jats:sub>\u03b1<jats:sub>1<\/jats:sub> pore-forming subunit and the accessory subunits Ca<jats:sub>v<\/jats:sub>\u03b2, Ca<jats:sub>v<\/jats:sub>\u03b1<jats:sub>2<\/jats:sub>\u03b4, and Ca<jats:sub>v<\/jats:sub>\u03b3. Ca<jats:sub>v<\/jats:sub>\u03b2 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<jats:sub>v<\/jats:sub>\u03b2 silencing, we demonstrate that Ca<jats:sub>v<\/jats:sub>\u03b2<jats:sub>2<\/jats:sub> downregulation enhances \u03b11-adrenergic receptor agonist-induced cardiomyocyte hypertrophy. We report that a pool of Ca<jats:sub>v<\/jats:sub>\u03b2<jats:sub>2<\/jats:sub> is targeted to the nucleus in cardiomyocytes and that the expression of this nuclear fraction decreases during <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> induction of cardiac hypertrophy. Moreover, the overexpression of nucleus-targeted Ca<jats:sub>v<\/jats:sub>\u03b2<jats:sub>2<\/jats:sub> in cardiomyocytes inhibits <jats:italic>in vitro<\/jats:italic>-induced hypertrophy. Quantitative proteomic analyses showed that Ca<jats:sub>v<\/jats:sub>\u03b2<jats:sub>2<\/jats: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<jats:sub>v<\/jats:sub>\u03b2<jats:sub>2<\/jats:sub>-downregulated cardiomyocytes had a 2-fold increase in calpain activity as compared to control cells. Furthermore, inhibition of calpain activity in Ca<jats:sub>v<\/jats:sub>\u03b2<jats:sub>2<\/jats:sub>-downregulated cells abolished the enhanced \u03b11-adrenergic receptor agonist-induced hypertrophy observed in these cells. Our findings indicate that in cardiomyocytes, a nuclear pool of Ca<jats:sub>v<\/jats:sub>\u03b2<jats:sub>2<\/jats:sub> participates in cellular functions that are independent of LTCC activity. They also indicate that a downregulation of nuclear Ca<jats:sub>v<\/jats:sub>\u03b2<jats:sub>2<\/jats:sub> during cardiomyocyte hypertrophy promotes the activation of calpain-dependent hypertrophic pathways.<\/jats:p>","DOI":"10.3389\/fcvm.2021.704657","type":"journal-article","created":{"date-parts":[[2021,7,7]],"date-time":"2021-07-07T05:17:42Z","timestamp":1625635062000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["The \u03b22-Subunit of Voltage-Gated Calcium Channels Regulates Cardiomyocyte 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