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PMID: 18599866 Published · ppublish English Journal Article

Protein kinase A-mediated phosphorylation of cMyBP-C increases proximity of myosin heads to actin in resting myocardium.

Circulation research ·Vol. 103 ·No. 3 ·2008-08-01 ·Pages 244-51

Colson BA, Bekyarova T, Locher MR, Fitzsimons DP, Irving TC, Moss RL

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, I(11)/I(10), 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 I(11)/I(10) (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 I(11)/I(10) 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.

MeSH Terms
Actins/metabolism Animals Carrier Proteins/metabolism,physiology Cyclic AMP-Dependent Protein Kinases/metabolism Heart/physiology Kinetics Mice Mice, Knockout Microfilament Proteins/metabolism Myocardial Contraction Myocardium/metabolism Myosins/metabolism Phosphorylation Scattering, Small Angle X-Ray Diffraction
Chemicals
Actins Carrier Proteins Microfilament Proteins myosin-binding protein C Cyclic AMP-Dependent Protein Kinases Myosins
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Colson Brett A
Department of Physiology, University of Wisconsin Medical School, Madison, WI, USA. bacolson@wisc.edu
Bekyarova Tanya
Locher Matthew R
Fitzsimons Daniel P
Irving Thomas C
Moss Richard L
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Article Info
Journal
Circulation research
Abbr.
Circ Res
ISSN
1524-4571
DOI
10.1161/CIRCRESAHA.108.178996
Email
bacolson@wisc.edu
Published
2008-08-01
Epub
2008-00-03
Pages
244-51
Language
English
Region
United States
NLM ID
0047103
PMCID
PMC2810832
Subset
IM
Grants
NCRR NIH HHS · P41 RR008630 · United States
NHLBI NIH HHS · R37 HL082900 · United States
NHLBI NIH HHS · R37 HL082900-01 · United States
External Links
PubMed source DOI: 10.1161/CIRCRESAHA.108.178996 PMC Full Text View journal details
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