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Phosphoregulation of Cardiac Inotropy via Myosin Binding Protein-C During Increased Pacing Frequency or ?1-Adrenergic Stimulation.

ABSTRACT: Mammalian hearts exhibit positive inotropic responses to ?-adrenergic stimulation as a consequence of protein kinase A-mediated phosphorylation or as a result of increased beat frequency (the Bowditch effect). Several membrane and myofibrillar proteins are phosphorylated under these conditions, but the relative contributions of these to increased contractility are not known. Phosphorylation of cardiac myosin-binding protein-C (cMyBP-C) by protein kinase A accelerates the kinetics of force development in permeabilized heart muscle, but its role in vivo is unknown. Such understanding is important because adrenergic responsiveness of the heart and the Bowditch effect are both depressed in heart failure.The roles of cMyBP-C phosphorylation were studied using mice in which either WT or nonphosphorylatable forms of cMyBP-C [ser273ala, ser282ala, ser302ala: cMyBP-C(t3SA)] were expressed at similar levels on a cMyBP-C null background. Force and [Ca(2+)]in measurements in isolated papillary muscles showed that the increased force and twitch kinetics because increased pacing or ?1-adrenergic stimulation were nearly absent in cMyBP-C(t3SA) myocardium, even though [Ca(2+)]in transients under each condition were similar to WT. Biochemical measurements confirmed that protein kinase A phosphorylated ser273, ser282, and ser302 in WT cMyBP-C. In contrast, CaMKII?, which is activated by increased pacing, phosphorylated ser302 principally, ser282 to a lesser degree, and ser273 not at all.Phosphorylation of cMyBP-C increases the force and kinetics of twitches in living cardiac muscle. Further, cMyBP-C is a principal mediator of increased contractility observed with ?-adrenergic stimulation or increased pacing because of protein kinase A and CaMKII? phosphorylations of cMyB-C.

SUBMITTER: Tong CW

PROVIDER: S-EPMC4439328 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Phosphoregulation of Cardiac Inotropy via Myosin Binding Protein-C During Increased Pacing Frequency or β1-Adrenergic Stimulation.

Tong Carl W CW Wu Xin X Liu Yang Y Rosas Paola C PC Sadayappan Sakthivel S Hudmon Andy A Muthuchamy Mariappan M Powers Patricia A PA Valdivia Héctor H HH Moss Richard L RL

Circulation. Heart failure 20150304 3

<h4>Background</h4>Mammalian hearts exhibit positive inotropic responses to β-adrenergic stimulation as a consequence of protein kinase A-mediated phosphorylation or as a result of increased beat frequency (the Bowditch effect). Several membrane and myofibrillar proteins are phosphorylated under these conditions, but the relative contributions of these to increased contractility are not known. Phosphorylation of cardiac myosin-binding protein-C (cMyBP-C) by protein kinase A accelerates the kinet ...[more]

PMID: 25740838

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Project description:In the presence of 5 microM-DL-propranolol and in HCO3(-)-containing buffers, 1 microM-adrenaline acutely stimulated protein synthesis by about 25% in the anterogradely perfused rat heart. This stimulation was opposed by low (1-10 nM) concentrations of prazosin, but not by similar concentrations of yohimbine, suggesting involvement of the alpha 1-adrenoceptor. Under the same conditions, adrenaline raised intracellular pH (pHi) by about 0.1 unit. The increase in pHi induced by adrenaline was prevented by 5 nM-prazosin, but not by 5 nM-yohimbine, again suggesting involvement of the alpha 1-adrenoceptor. Since an increase in pHi stimulates protein synthesis in the heart [Sugden & Fuller (1991) Biochem. J. 273, 339-346], the increase in pHi induced by adrenaline may be involved in its stimulation of protein synthesis. Adrenaline also increased phosphocreatine concentrations. As discussed, the increase in pHi induced by adrenaline may be responsible for this effect. Using second-order polynomial regression analysis, we showed that rates of protein synthesis were significantly correlated (P less than 0.0001) with phosphocreatine concentrations. We discuss two possible reasons for this correlation: (i) increases in pHi stimulate protein synthesis and separately raise phosphocreatine concentrations, or (ii) the increase in protein synthesis rates is a consequence of the raised phosphocreatine concentrations induced by the increase in pHi. Rates of protein synthesis were not significantly correlated with ATP/ADP concentration ratios, nor with any of the following: ATP, ADP, AMP or total adenine nucleotide concentrations. In freshly isolated adult rat cardiomyocytes, the protein kinase inhibitor staurosporine (1 microM) prevented stimulation of protein synthesis by 0.3 microM-adrenaline (and by 1 microM-phorbol 12-myristate 13-acetate or 1 m-unit of insulin/ml). The results are discussed within a mechanistic framework initiated by stimulation of the hydrolysis of membrane phospholipids by alpha 1-adrenergic agonists.

Dataset Information

Phosphoregulation of Cardiac Inotropy via Myosin Binding Protein-C During Increased Pacing Frequency or ?1-Adrenergic Stimulation.

Publications

Phosphoregulation of Cardiac Inotropy via Myosin Binding Protein-C During Increased Pacing Frequency or β1-Adrenergic Stimulation.

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