title: Cardiac function is regulated by B56α-mediated targeting of protein phosphatase 2A (PP2A) to contractile relevant substrates.
abstract: 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 B56α, a phosphoprotein of the PP2A-B56 family. The 2-fold overexpression of B56α 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 β-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-B56α 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 β-adrenergic stimulation.
authors.affiliation: From the Institut für Pharmakologie und Toxikologie, Universitätsklinikum Münster, D-48149 Münster, Germany and kirchhef@uni-muenster.de.
authors.forename: Uwe
authors.initials: U
authors.lastname: Kirchhefer
authors.affiliation: From the Institut für Pharmakologie und Toxikologie, Universitätsklinikum Münster, D-48149 Münster, Germany and.
authors.forename: Christiane
authors.initials: C
authors.lastname: Brekle
authors.affiliation: From the Institut für Pharmakologie und Toxikologie, Universitätsklinikum Münster, D-48149 Münster, Germany and.
authors.forename: John
authors.initials: J
authors.lastname: Eskandar
authors.affiliation: From the Institut für Pharmakologie und Toxikologie, Universitätsklinikum Münster, D-48149 Münster, Germany and.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Isensee
authors.affiliation: From the Institut für Pharmakologie und Toxikologie, Universitätsklinikum Münster, D-48149 Münster, Germany and.
authors.forename: Dana
authors.initials: D
authors.lastname: Kučerová
authors.affiliation: From the Institut für Pharmakologie und Toxikologie, Universitätsklinikum Münster, D-48149 Münster, Germany and.
authors.forename: Frank U
authors.initials: FU
authors.lastname: Müller
authors.affiliation: INSERM, U744, Institut Pasteur de Lille, 59019 Lille, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Pinet
authors.affiliation: From the Institut für Pharmakologie und Toxikologie, Universitätsklinikum Münster, D-48149 Münster, Germany and.
authors.forename: Jan S
authors.initials: JS
authors.lastname: Schulte
authors.affiliation: From the Institut für Pharmakologie und Toxikologie, Universitätsklinikum Münster, D-48149 Münster, Germany and.
authors.forename: Matthias D
authors.initials: MD
authors.lastname: Seidl
authors.affiliation: From the Institut für Pharmakologie und Toxikologie, Universitätsklinikum Münster, D-48149 Münster, Germany and.
authors.forename: Peter
authors.initials: P
authors.lastname: Boknik
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009210:Myofibrils / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D055503:Protein Multimerization; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D019210:Troponin I / Q000235:genetics / Q000378:metabolism*; D000099211:Phospholamban; D000099163:Myosin Binding Protein C
chemical_list: D000318:Adrenergic beta-Agonists; D002118:Calcium; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D007545:Isoproterenol; D054648:Protein Phosphatase 2; D019210:Troponin I; D000099211:Phospholamban; D000099163:Myosin Binding Protein C; C551901:Ppp2r5a protein, mouse
keywords: Adrenergic Receptor; Cardiomyocyte; Contractile Protein; Protein Phosphatase 2 (PP2A); Protein Phosphorylation