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Circ Heart Fail. 2015 May;8(3):595-604. doi: 10.1161/CIRCHEARTFAILURE.114.001585. Epub 2015 Mar 4.

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

Author information

1
From the Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison (C.W.T., P.A.P., R.L.M.); Department of Medical Physiology (C.W.T., Y.L., P.C.R., M.M.) and Neuroscience and Experimental Therapeutics (X.W.), Texas A&M University Health Science Center College of Medicine, Temple; Baylor Scott & White Health, Temple, TX (C.W.T.); Department of Physiology, Loyola University Chicago Stritch School of Medicine, IL (S.S.); Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis (A.H.); and Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor (H.H.V.).
2
From the Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison (C.W.T., P.A.P., R.L.M.); Department of Medical Physiology (C.W.T., Y.L., P.C.R., M.M.) and Neuroscience and Experimental Therapeutics (X.W.), Texas A&M University Health Science Center College of Medicine, Temple; Baylor Scott & White Health, Temple, TX (C.W.T.); Department of Physiology, Loyola University Chicago Stritch School of Medicine, IL (S.S.); Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis (A.H.); and Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor (H.H.V.). rlmoss@wisc.edu.

Abstract

BACKGROUND:

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 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.

METHODS AND RESULTS:

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 β1-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, CaMKIIδ, which is activated by increased pacing, phosphorylated ser302 principally, ser282 to a lesser degree, and ser273 not at all.

CONCLUSIONS:

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 β-adrenergic stimulation or increased pacing because of protein kinase A and CaMKIIδ phosphorylations of cMyB-C.

KEYWORDS:

contractility; myosin-binding protein-C; phosphorylation

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