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@ARTICLE{Pickel:893930,
      author       = {Pickel, Simone and Cruz-Garcia, Yiliam and Bandleon, Sandra
                      and Barkovits, Katalin and Heindl, Cornelia and Völker,
                      Katharina and Abeßer, Marco and Pfeiffer, Kathy and Schaaf,
                      Alice and Marcus, Katrin and Eder-Negrin, Petra and Kuhn,
                      Michaela and Miranda Laferte, Erick},
      title        = {{T}he β$_{2}$-{S}ubunit of {V}oltage-{G}ated {C}alcium
                      {C}hannels {R}egulates {C}ardiomyocyte {H}ypertrophy},
      journal      = {Frontiers in Cardiovascular Medicine},
      volume       = {8},
      issn         = {2297-055X},
      address      = {Lausanne},
      publisher    = {Frontiers Media},
      reportid     = {FZJ-2021-02940},
      pages        = {704657},
      year         = {2021},
      abstract     = {L-type voltage-gated calcium channels (LTCCs) regulate
                      crucial physiological processes in the heart. They are
                      composed of the Cavα1 pore-forming subunit and the
                      accessory subunits Cavβ, Cavα2δ, and Cavγ. Cavβ 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 Cavβ silencing, we
                      demonstrate that Cavβ2 downregulation enhances
                      α1-adrenergic receptor agonist-induced cardiomyocyte
                      hypertrophy. We report that a pool of Cavβ2 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 Cavβ2 in cardiomyocytes
                      inhibits in vitro-induced hypertrophy. Quantitative
                      proteomic analyses showed that Cavβ2 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,
                      Cavβ2-downregulated cardiomyocytes had a 2-fold increase in
                      calpain activity as compared to control cells. Furthermore,
                      inhibition of calpain activity in Cavβ2-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
                      Cavβ2 participates in cellular functions that are
                      independent of LTCC activity. They also indicate that a
                      downregulation of nuclear Cavβ2 during cardiomyocyte
                      hypertrophy promotes the activation of calpain-dependent
                      hypertrophic pathways.},
      cin          = {IBI-1},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IBI-1-20200312},
      pnm          = {5243 - Information Processing in Distributed Systems
                      (POF4-524)},
      pid          = {G:(DE-HGF)POF4-5243},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {34307509},
      UT           = {WOS:000674908500001},
      doi          = {10.3389/fcvm.2021.704657},
      url          = {https://juser.fz-juelich.de/record/893930},
}