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(Circulation Research. 2006;98:1290.)
© 2006 American Heart Association, Inc.

Cellular Biology

Activation of Myocardial Contraction by the N-Terminal Domains of Myosin Binding Protein-C

Todd J. Herron, Elena Rostkova, Gudrun Kunst, Rajiv Chaturvedi, Mathias Gautel, Jonathan C. Kentish

From the Cardiovascular Division (T.J.H., E.R., R.C., M.G., 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.

Correspondence to Jonathan C. Kentish, MA, PhD, Cardiovascular Division, King’s College London, Rayne Institute, St. Thomas’ Hospital, London, SE1 7EH, United Kingdom. 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 (k_tr) 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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