Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 53, Issue 5, Pages 609-616Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2012.07.012
Keywords
Myosin binding protein C; Troponin 1; Cross-bridge cycling kinetics; Protein kinase A; Phosphorylation; Low-angle X-ray diffraction
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Funding
- American Heart Association
- NIH [HL-R37-82900]
- U.S. Department of Energy, Basic Energy Sciences, Office of Science [W-31-109-ENG-38]
- National Center for Research Resources [2P41RR008630]
- National Institute of General Medical Sciences [941GM103622]
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Phosphorylation of cardiac myosin binding protein-C (cMyBP-C) is a regulator of pump function in healthy hearts. However, the mechanisms of regulation by CAMP-dependent protein kinase (PKA)-mediated cMyBP-C phosphorylation have not been completely dissociated from other myofilament substrates for PKA, especially cardiac troponin I (cTnI). We have used synchrotron X-ray diffraction in skinned trabeculae to elucidate the roles of cMyBP-C and cTnI phosphorylation in myocardial inotropy and lusitropy. Myocardium in this study was isolated from four transgenic mouse lines in which the phosphorylation state of either cMyBP-C or cTnI was constitutively altered by site-specific mutagenesis. Analysis of peak intensities in X-ray diffraction patterns from trabeculae showed that cross-bridges are displaced similarly from the thick filament and toward actin (1) when both cMyBP-C and cTnI are phosphorylated, (2) when only cMyBP-C is phosphorylated, and (3) when cMyBP-C phosphorylation is mimicked by replacement with negative charge in its PKA sites. These findings suggest that phosphorylation of cMyBP-C relieves a constraint on cross-bridges, thereby increasing the proximity of myosin to binding sites on actin. Measurements of Ca2+-activated force in myocardium defined distinct molecular effects due to phosphorylation of cMyBP-C or co-phosphorylation with cTnl. Echocardiography revealed that mimicking the charge of cMyBP-C phosphorylation protects hearts from hypertrophy and systolic dysfunction that develops with constitutive dephosphorylation or genetic ablation, underscoring the importance of cMyBP-C phosphorylation for proper pump function. Published by Elsevier Ltd.
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