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(Circulation Research. 2008;103:244.)
© 2008 American Heart Association, Inc.

Molecular Medicine

Protein Kinase A–Mediated Phosphorylation of cMyBP-C Increases Proximity of Myosin Heads to Actin in Resting Myocardium

Brett A. Colson, Tanya Bekyarova, Matthew R. Locher, Daniel P. Fitzsimons, Thomas C. Irving, Richard L. Moss

From the Department of Physiology (B.A.C., M.R.L., D.P.F., R.L.M.), University of Wisconsin Medical School, Madison, Wis; and CSRRI and the Department of BCPS (T.B., T.C.I.), Illinois Institute of Technology, Chicago, Ill.

Correspondence to Brett Colson, 601 Science Drive, Madison, WI 53711. E-mail bacolson{at}wisc.edu

Protein kinase A–mediated (PKA) phosphorylation of cardiac myosin binding protein C (cMyBP-C) accelerates the kinetics of cross-bridge cycling and may relieve the tether-like constraint of myosin heads imposed by cMyBP-C. We favor a mechanism in which cMyBP-C modulates cross-bridge cycling kinetics by regulating the proximity and interaction of myosin and actin. To test this idea, we used synchrotron low-angle x-ray diffraction to measure interthick filament lattice spacing and the equatorial intensity ratio, I₁₁/I₁₀, in skinned trabeculae isolated from wild-type and cMyBP-C null (cMyBP-C^–/–) mice. In wild-type myocardium, PKA treatment appeared to result in radial or azimuthal displacement of cross-bridges away from the thick filaments as indicated by an increase (approximately 50%) in I₁₁/I₁₀ (0.22±0.03 versus 0.33±0.03). Conversely, PKA treatment did not affect cross-bridge disposition in mice lacking cMyBP-C, because there was no difference in I₁₁/I₁₀ between untreated and PKA-treated cMyBP-C^–/– myocardium (0.40±0.06 versus 0.42±0.05). Although lattice spacing did not change after treatment in wild-type (45.68±0.84 nm versus 45.64±0.64 nm), treatment of cMyBP-C^–/– myocardium increased lattice spacing (46.80±0.92 nm versus 49.61±0.59 nm). This result is consistent with the idea that the myofilament lattice expands after PKA phosphorylation of cardiac troponin I, and when present, cMyBP-C, may stabilize the lattice. These data support our hypothesis that tethering of cross-bridges by cMyBP-C is relieved by phosphorylation of PKA sites in cMyBP-C, thereby increasing the proximity of cross-bridges to actin and increasing the probability of interaction with actin on contraction.

Key Words: contractile protein structure • cross-bridge kinetics • cMyBP-C • protein kinase A phosphorylation • x-ray

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