期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 289, 期 49, 页码 33862-33873出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.598938
关键词
Adrenergic Receptor; Cardiomyocyte; Contractile Protein; Protein Phosphatase 2 (PP2A); Protein Phosphorylation
资金
- Innovative Medizinische Forschung Munster [KI 2 1 10 10]
Background: PP2A is a regulator of cardiac excitation-contraction coupling. Results: Cardiomyocyte-directed overexpression of B56, the main cardiac PP2A regulatory subunit, results in the dephosphorylation of myofilament proteins, increased Ca2+ sensitivity, and higher contractility. Conclusion: This suggests an important role for B56 in regulating PP2A activity and thereby the contractile function. Significance: PP2A-B56 is a potential pharmacological target to improve cardiac performance in failing hearts. 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 B56, a phosphoprotein of the PP2A-B56 family. The 2-fold overexpression of B56 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 -adrenergic receptors by isoproterenol (ISO) resulted in an impaired contractile response of TG hearts. At a depolarizing potential of -5 mV, the I-Ca,I-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-B56 activity in TG hearts is localized to specific subcellular sites leading to the dephosphorylation of important contractile proteins. This may result in higher myofilament Ca2+ sensitivity and increased basal contractility in TG hearts. These effects were reversed by -adrenergic stimulation.
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