Activation of myocardial contraction by the N-terminal domains of myosin binding protein-C.
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 micromol/L, the N-terminal C0C2 peptide activated force production in the absence of calcium (pCa 9). Force at the optimal concentration (80 micromol/L) of C0C2 was approximately 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 micromol/L), exogenous C0C2 strongly sensitized cardiac myofibrils to Ca2+ at a sarcomere length (SL) of 1.9 microm but had no significant effect at SL 2.3 microm. 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 micromol/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.
Herron
Todd J
TJ
Cardiovascular Division, King's College London, London, UK.
Rostkova
Elena
E
Kunst
Gudrun
G
Chaturvedi
Rajiv
R
Gautel
Mathias
M
Kentish
Jonathan C
JC
D000818:Animals; D002118:Calcium / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D006352:Heart Ventricles; D006801:Humans; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009210:Myofibrils / Q000502:physiology; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D051381:Rats; D012518:Sarcomeres / Q000187:drug effects / Q000648:ultrastructure; D014018:Tissue Distribution; D000099163:Myosin Binding Protein C
D002118:Calcium; D002352:Carrier Proteins; D010446:Peptide Fragments; D000099163:Myosin Binding Protein C