Phosphoregulation of Cardiac Inotropy via Myosin Binding Protein-C During Increased Pacing Frequency or 1-Adrenergic Stimulation.
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BACKGROUND: 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. 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 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. 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 -adrenergic stimulation or increased pacing because of protein kinase A and CaMKII phosphorylations of cMyB-C.
author list (cited authors)
Tong, C. W., Wu, X., Liu, Y., Rosas, P. C., Sadayappan, S., Hudmon, A., ... Moss, R. L.
complete list of authors
Tong, Carl W||Wu, Xin||Liu, Yang||Rosas, Paola C||Sadayappan, Sakthivel||Hudmon, Andy||Muthuchamy, Mariappan||Powers, Patricia A||Valdivia, Héctor H||Moss, Richard L