Cardiac myosin binding protein-C Ser phosphorylation regulates cardiac b-adrenergic reserve

Phosphorylation of cardiac myosin binding protein-C (MyBP-C) modulates cardiac contractile function; however, the specific roles of individual serines (Ser) within theM-domain that are targets for b-adrenergic signaling are not known. Recently, we demonstrated that significant accelerations in in vivo pressure development following b-agonist infusion can occur in transgenic (TG) mouse hearts expressing phospho-ablated Ser (that is, TG) but not in hearts expressing phospho-ablation of all three serines [that is, Ser, Ser, and Ser (TG)], suggesting an important modulatory role for other Ser residues. In this regard, there is evidence that Ser phosphorylation may be a key contributor to the b-agonist–induced positive inotropic responses in themyocardium, but its precise functional role has not been established. Thus, to determine the in vivo and in vitro functional roles of Ser phosphorylation, we generated TGmice expressing nonphosphorylatable Ser (that is, TG). Left ventricular pressure-volumemeasurements revealed that TG mice displayed no accelerations in the rate of systolic pressure rise and an inability to maintain systolic pressure following dobutamine infusion similar to TG mice, implicating Ser phosphorylation as a critical regulator of enhanced systolic performance during b-adrenergic stress. Dynamic strain–induced cross-bridge (XB) measurements in skinned myocardium isolated from TG hearts showed that the molecular basis for impaired b-adrenergic–mediated enhancements in systolic function is due to the absence of protein kinase A–mediated accelerations in the rate of cooperative XB recruitment. These results demonstrate that Ser phosphorylation regulates cardiac contractile reserve by enhancing contractile responses during b-adrenergic stress. p://a