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

Research output: Contribution to journalArticle

71 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)244-251
Number of pages8
JournalCirculation research
Volume103
Issue number3
DOIs
StatePublished - Aug 1 2008

Keywords

  • CMyBP-C
  • Contractile protein structure
  • Cross-bridge kinetics
  • Protein kinase A phosphorylation
  • X-ray

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