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(Circulation Research. 2007;101:503.)
© 2007 American Heart Association, Inc.

Cellular Biology

Differential Roles of Cardiac Myosin-Binding Protein C and Cardiac Troponin I in the Myofibrillar Force Responses to Protein Kinase A Phosphorylation

Julian E. Stelzer, Jitandrakumar R. Patel, Jeffery W. Walker, Richard L. Moss

From the Department of Physiology, University of Wisconsin School of Medicine and Public Health, Madison.

Correspondence to Julian E. Stelzer, Department of Physiology, University of Wisconsin Medical School, 601 Science Dr, Madison, WI 53711. E-mail stelzer{at}physiology.wisc.edu

The heart is remarkably adaptable in its ability to vary its function to meet the changing demands of the circulatory system. During times of physiological stress, cardiac output increases in response to increased sympathetic activity, which results in protein kinase A (PKA)-mediated phosphorylations of the myofilament proteins cardiac troponin (cTn)I and cardiac myosin-binding protein (cMyBP)-C. Despite the importance of this mechanism, little is known about the relative contributions of cTnI and cMyBP-C phosphorylation to increased cardiac contractility. Using engineered mouse lines either lacking cMyBP-C (cMyBP-C^–/–) or expressing a non-PKA phosphorylatable cTnI (cTnI_ala2), or both (cMyBP-C^–/–/cTnI_ala2), we investigated the roles of cTnI and cMyBP-C phosphorylation in the regulation of the stretch-activation response. PKA treatment of wild-type and cTnI_ala2 skinned ventricular myocardium accelerated stretch activation such that the response was indistinguishable from stretch activation of cMyBP-C^–/– or cMyBP-C^–/–/cTnI_ala2 myocardium; however, PKA had no effect on stretch activation in cMyBP-C^–/– or cMyBP-C^–/–/cTnI_ala2 myocardium. These results indicate that the acceleration of stretch activation in wild-type and cTnI_ala2 myocardium is caused by phosphorylation of cMyBP-C and not cTnI. We conclude that the primary effect of PKA phosphorylation of cTnI is reduced Ca²⁺ sensitivity of force, whereas phosphorylation of cMyBP-C accelerates the kinetics of force development. These results predict that PKA phosphorylation of myofibrillar proteins in living myocardium contributes to accelerated relaxation in diastole and increased rates of force development in systole.

Key Words: cross-bridge kinetics • ß-adrenergic agonists • positive inotropy • contractile protein function

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