| First Author | Kirchhefer U | Year | 2014 |
| Journal | J Biol Chem | Volume | 289 |
| Issue | 49 | Pages | 33862-73 |
| PubMed ID | 25320082 | Mgi Jnum | J:218294 |
| Mgi Id | MGI:5617124 | Doi | 10.1074/jbc.M114.598938 |
| Citation | Kirchhefer U, et al. (2014) Cardiac function is regulated by B56alpha-mediated targeting of protein phosphatase 2A (PP2A) to contractile relevant substrates. J Biol Chem 289(49):33862-73 |
| abstractText | Dephosphorylation of important myocardial proteins is regulated by protein phosphatase 2A (PP2A), representing a heterotrimer that is comprised of catalytic, scaffolding, and regulatory (B) subunits. There is a multitude of B subunit family members directing the PP2A holoenzyme to different myocellular compartments. To gain a better understanding of how these B subunits contribute to the regulation of cardiac performance, we generated transgenic (TG) mice with cardiomyocyte-directed overexpression of B56alpha, a phosphoprotein of the PP2A-B56 family. The 2-fold overexpression of B56alpha was associated with an enhanced PP2A activity that was localized mainly in the cytoplasm and myofilament fraction. Contractility was enhanced both at the whole heart level and in isolated cardiomyocytes of TG compared with WT mice. However, peak amplitude of [Ca]i did not differ between TG and WT cardiomyocytes. The basal phosphorylation of cardiac troponin inhibitor (cTnI) and the myosin-binding protein C was reduced by 26 and 35%, respectively, in TG compared with WT hearts. The stimulation of beta-adrenergic receptors by isoproterenol (ISO) resulted in an impaired contractile response of TG hearts. At a depolarizing potential of -5 mV, the ICa,L current density was decreased by 28% after administration of ISO in TG cardiomyocytes. In addition, the ISO-stimulated phosphorylation of phospholamban at Ser(16) was reduced by 27% in TG hearts. Thus, the increased PP2A-B56alpha activity in TG hearts is localized to specific subcellular sites leading to the dephosphorylation of important contractile proteins. This may result in higher myofilament Ca(2+) sensitivity and increased basal contractility in TG hearts. These effects were reversed by beta-adrenergic stimulation. |
