Protein kinase A-induced myofilament desensitization to Ca2+ as a result of phosphorylation of cardiac myosin-binding protein C

被引:56
作者
Chen, Peter P. [1 ,2 ]
Patel, Jitandrakumar R. [1 ,2 ]
Rybakova, Inna N. [1 ,2 ]
Walker, Jeffery W. [3 ,4 ]
Moss, Richard L. [1 ,2 ]
机构
[1] Univ Wisconsin, Dept Physiol, Sch Med & Publ Hlth, Madison, WI 53706 USA
[2] Univ Wisconsin, UW Cardiovasc Res Ctr, Sch Med & Publ Hlth, Madison, WI 53706 USA
[3] Univ Arizona, Dept Physiol, Tucson, AZ 85724 USA
[4] Univ Arizona, Mol Cardiovasc Res Program, Tucson, AZ 85724 USA
关键词
TROPONIN-I PHOSPHORYLATION; FAMILIAL HYPERTROPHIC CARDIOMYOPATHY; MURINE SKINNED MYOCARDIUM; REGULATORY LIGHT-CHAIN; FORCE DEVELOPMENT; CROSSBRIDGE KINETICS; DIFFERENTIAL ROLES; STRETCH ACTIVATION; MOUSE MYOCARDIUM; MUSCLE-FIBERS;
D O I
10.1085/jgp.201010448
中图分类号
Q4 [生理学];
学科分类号
071003 ;
摘要
In skinned myocardium, cyclic AMP-dependent protein kinase A (PKA)-catalyzed phosphorylation of cardiac myosin-binding protein C (cMyBP-C) and cardiac troponin I (cTnI) is associated with a reduction in the Ca2+ responsiveness of myofilaments and an acceleration in the kinetics of cross-bridge cycling, although the respective contribution of these two proteins remains controversial. To further examine the relative roles that cTnI and cMyBP-C phosphorylation play in altering myocardial function, we determined the Ca2+ sensitivity of force (pCa(50)) and the activation dependence of the rate of force redevelopment (k(tr)) in control and PKA-treated mouse myocardium (isolated in the presence of 2,3-butanedione monoxime) expressing: (a) phosphorylatable cTnI and cMyBP-C (wild type [WT]), (b) phosphorylatable cTnI on a cMyBP-C-null background (cMyBP-C-/-), (c) nonphosphorylatable cTnI with serines(23/24/43/45) and threonine(144) mutated to alanines (cTnI(Ala5)), and (d) nonphosphorylatable cTnI on a cMyBP-C-null background (cTnI(Ala5)/cMyBP-C-/-). Here, PKA treatment decreased pCa(50) in WT, cTnI(Ala5), and cMyBP-C-/- myocardium by 0.13, 0.08, and 0.09 pCa units, respectively, but had no effect in cTnI(Ala5)/cMyBP-C-/- myocardium. In WT and cTnI(Ala5) myocardium, PKA treatment also increased k(tr) at submaximal levels of activation; however, PKA treatment did not have an effect on k(tr) in cMyBP-C-/- or cTnI(Ala5)/cMyBP-C-/- myocardium. In addition, reconstitution of cTnI(Ala5)/cMyBP-C-/- myocardium with recombinant cMyBP-C restored the effects of PKA treatment on pCa(50) and k(tr) reported in cTnI(Ala5) myocardium. Collectively, these results indicate that the attenuation in myofilament force response to PKA occurs as a result of both cTnI and cMyBP-C phosphorylation, and that the reduction in pCa(50) mediated by cMyBP-C phosphorylation most likely arises from an accelerated cross-bridge cycling kinetics partly as a result of an increased rate constant of cross-bridge detachment.
引用
收藏
页码:615 / 627
页数:13
相关论文
共 45 条
  • [1] Distinct Sarcomeric Substrates Are Responsible for Protein Kinase D-mediated Regulation of Cardiac Myofilament Ca2+ Sensitivity and Cross-bridge Cycling
    Bardswell, Sonya C.
    Cuello, Friederike
    Rowland, Alexandra J.
    Sadayappan, Sakthivel
    Robbins, Jeffrey
    Gautel, Mathias
    Walker, Jeffery W.
    Kentish, Jonathan C.
    Avkiran, Metin
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2010, 285 (08) : 5674 - 5682
  • [2] Cardiac excitation-contraction coupling
    Bers, DM
    [J]. NATURE, 2002, 415 (6868) : 198 - 205
  • [3] SLControl: PC-based data acquisition and analysis for muscle mechanics
    Campbell, KS
    Moss, RL
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2003, 285 (06): : H2857 - H2864
  • [4] Length and protein kinase A modulations of myocytes in cardiac myosin binding protein C-deficient mice
    Cazorla, O
    Szilagyi, S
    Vignier, N
    Salazar, G
    Krämer, E
    Vassort, G
    Carrier, L
    Lacampagne, A
    [J]. CARDIOVASCULAR RESEARCH, 2006, 69 (02) : 370 - 380
  • [5] Protein kinase A-mediated phosphorylation of cMyBP-C increases proximity of myosin heads to actin in resting myocardium
    Colson, Brett A.
    Bekyarova, Tanya
    Locher, Matthew R.
    Fitzsimons, Daniel P.
    Irving, Thomas C.
    Moss, Richard L.
    [J]. CIRCULATION RESEARCH, 2008, 103 (03) : 244 - 251
  • [6] Radial displacement of myosin cross-bridges in mouse myocardium due to ablation of myosin binding protein-C
    Colson, Brett A.
    Bekyarova, Tanya
    Fitzsimons, Daniel P.
    Irving, Thomas C.
    Moss, Richard L.
    [J]. JOURNAL OF MOLECULAR BIOLOGY, 2007, 367 (01) : 36 - 41
  • [7] Differential roles of regulatory light chain and myosin binding protein-C phosphorylations in the modulation of cardiac force development
    Colson, Brett A.
    Locher, Matthew R.
    Bekyarova, Tanya
    Patel, Jitandrakumar R.
    Fitzsimons, Daniel P.
    Irving, Thomas C.
    Moss, Richard L.
    [J]. JOURNAL OF PHYSIOLOGY-LONDON, 2010, 588 (06): : 981 - 993
  • [8] PROTEIN-KINASE A DOES NOT ALTER ECONOMY OF FORCE MAINTENANCE IN SKINNED RAT CARDIAC TRABECULAE
    DETOMBE, PP
    STIENEN, GJM
    [J]. CIRCULATION RESEARCH, 1995, 76 (05) : 734 - 741
  • [9] Impaired cardiomyocyte relaxation and diastolic function in transgenic mice expressing slow skeletal troponin I in the heart
    F'entzke, RC
    Buck, SH
    Patel, JR
    Lin, H
    Wolska, BM
    Stojanovic, MO
    Martin, AF
    Solaro, RJ
    Moss, RL
    Leiden, JM
    [J]. JOURNAL OF PHYSIOLOGY-LONDON, 1999, 517 (01): : 143 - 157
  • [10] FABIATO A, 1988, METHOD ENZYMOL, V157, P378, DOI DOI 10.1016/0076-6879(88)57093-3