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

被引:95
作者
Colson, Brett A. [1 ]
Bekyarova, Tanya [2 ,3 ]
Locher, Matthew R. [1 ]
Fitzsimons, Daniel P. [1 ]
Irving, Thomas C. [2 ,3 ]
Moss, Richard L. [1 ]
机构
[1] Univ Wisconsin, Sch Med, Dept Physiol, Madison, WI 53706 USA
[2] IIT, CSRRI, Chicago, IL 60616 USA
[3] IIT, Dept BCPS, Chicago, IL 60616 USA
关键词
contractile protein structure; cross-bridge kinetics; cMyBP-C; protein kinase A phosphorylation; x-ray;
D O I
10.1161/CIRCRESAHA.108.178996
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:244 / 251
页数:8
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