The duration of the contraction, the velocity of shortening, the rate of hydrolysis of ATP and the efficiency of the conversion of chemical to hydrodynamic energy can each be varied as the heart meets the requirements of the organism without jeopardizing its own viability. Modulation of contraction can occur from changes in Ca cycling or myofilament structure. Although almost every transmitter-based physiological mechanism for altering cardiac contractility is accompanied by phosphorylation of C protein and in several cases the regulatory light chain of myosin (LC2), little is known about the effects of these phosphorylations, singly or in combination, on contraction. Preliminary data indicate that phosphorylation of C protein is important in the modification of the kinetics of cross bridge cycling and the regulation of the efficiency of contraction. The goals of this proposal are to study: 1) the effects of phosphorylation of C protein alone and in combination with phosphorylation of LC2 on the contraction of the cardiac myocytes, in particular their efficiency; and 2) the relation of the changes in contraction to detectable changes in cross bridge structure. Three hypotheses will be evaluated: 1) Phosphorylation of C protein by PKA increases the rate of cross bridge cycling and decreases the efficiency of contraction; 2) Phosphorylation of LC2 with phosphorylation of C protein by PKC decreases the rate of cross bridge cycling and increases the efficiency of contraction; 3) The changes in cross bridge structure produced by the phosphorylations are consistent with the changes in the kinetics of cross bridge cycling. Relationships between contractile force, work, velocity, stiffness, ATP hydrolysis, efficiency and the phosphorylation of myofilament proteins and structure of cross bridges will be determined. The last will be examined in isolated thick filaments by electron microscopy and optical diffraction, and in skinned and intact fibers by x ray diffraction. Knowledge of the physiological mechanisms that modulate the economy and the efficiency of contraction is important for the management of disparities between the rate of energy supplied and the work done by the heart. By elucidating the relation among changes in energy use, phosphorylation of C protein and cross bridge structure in response to second messenger systems operating through protein kinases A and C, these studies will provide the basis for new pharmacological management of myocardial ischemia in both early and later stages.
| Decker, Robert S; Nakamura, Sakie; Decker, Marlene L et al. (2012) The dynamic role of cardiac myosin binding protein-C during ischemia. J Mol Cell Cardiol 52:1145-54 |
| Kulikovskaya, Irina; McClellan, George B; Levine, Rhea et al. (2007) Multiple forms of cardiac myosin-binding protein C exist and can regulate thick filament stability. J Gen Physiol 129:419-28 |
| Decker, Robert S; Decker, Marlene L; Kulikovskaya, Irina et al. (2005) Myosin-binding protein C phosphorylation, myofibril structure, and contractile function during low-flow ischemia. Circulation 111:906-12 |
