Abstract 3846: Hierarchical and Critical Functions of Ser282 Phosphorylation in Cardiac Myosin Binding Protein-C Phosphorylation and Cardiac Function

Background: Cardiac myosin binding protein-C (cMyBP-C) phosphorylation at Ser273, Ser282 and Ser302 regulates myocardial function and can be cardioprotective during heart failure. PKA, PKC and CaMKII phosphorylate these sites in vivo. The objective of this study was to differentiate the roles of the three sites in cMyBP-C phosphorylation and its consequences. Hypothesis: Ser282 in cMyBP-C regulates Ser273 and Ser302 phosphorylation and myocardial function during β-adrenergic stimulation. Methods: C1C2 peptides of cMyBP-C in which the three phosphorylatable sites were individually mutated to Ala, as well as a wild-type control, were used in conjunction with site-specific phospho antibodies to determine the targeting of these sites by PKA and CaMKII. To demonstrate regulation of the sites during heart failure, a transverse aortic constriction (TAC) mouse model was used. To determine the sites’ functional roles in vivo, three transgenic lines, which expressed cMyBP-C containing Ser273-Ala282-Ser302 (SAS), Al...