Published online before print April 13, 2006, doi: 10.1161/01.RES.0000222059.54917.ef
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Submitted on November 24, 2005
Revised on March 17, 2006
Accepted on March 31, 2006
Activation of Myocardial Contraction by the N-Terminal Domains of Myosin Binding Protein-C
Todd J. Herron ;
From the Cardiovascular Division (T.J.H., R.C., J.C.K.), King’s College London, St. Thomas’ Campus; Department of Anaesthesia (G.K.), King’s College Hospital, Denmark Hill Campus, London; and The Randall Centre (E.R., M.G.), New Hunt’s House, King’s College London, UK. Present address for T.J.H.: Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor. Present address for R.C.: Division of Cardiology, Hospital for Sick Children, Toronto, Ontario, Canada.
* To whom correspondence should be addressed. E-mail: jon.kentish{at}kcl.ac.uk.
Myosin binding protein-C (MyBP-C) is a poorly understood component of the thick filament in striated muscle sarcomeres. Its C terminus binds tightly to myosin, whereas the N terminus contains binding sites for myosin S2 and possibly for the thin filament. To study the role of the N-terminal domains of cardiac MyBP-C (cMyBP-C), we added human N-terminal peptide fragments to human and rodent skinned ventricular myocytes. At concentrations >10 µmol/L, the N-terminal C0C2 peptide activated force production in the absence of calcium (pCa 9). Force at the optimal concentration (80 µmol/L) of C0C2 was 
60% of that in maximal Ca2+ (pCa 4.5), but the rate constant of tension redevelopment (ktr) matched or exceeded (by up to 80%) that produced by Ca2+ alone. Experiments using different N-terminal peptides suggested that this activating effect of C0C2 resulted from binding by the pro/ala-rich C0-C1 linker region, rather than the terminal C0 domain. At a lower concentration (1 µmol/L), exogenous C0C2 strongly sensitized cardiac myofibrils to Ca2+ at a sarcomere length (SL) of 1.9 µm but had no significant effect at SL 2.3 µm. This differential effect caused the normal SL dependence of myofibrillar Ca2+ sensitivity to be reduced by 80% (mouse myocytes) or abolished (human myocytes) in 1 µmol/L C0C2. These results suggest that cMyBP-C provides a regulatory pathway by which the thick filament can influence the activation of the thin filament, separately from its regulation by Ca2+. Furthermore, the N-terminal region of cMyBP-C can influence the SL-tension (Frank-Starling) relationship in cardiac muscle.
Key words: myosin binding protein C • cardiac myocytes • Ca2+ sensitization • sarcomere length • Frank-Starling mechanism
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