Published online before print July 19, 2007, doi: 10.1161/CIRCRESAHA.107.153650
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on February 6, 2007
Revised on July 6, 2007
Accepted on July 9, 2007
Differential Roles of Cardiac Myosin-Binding Protein C and Cardiac Troponin I in the Myofibrillar Force Responses to Protein Kinase A Phosphorylation
Julian E. Stelzer *;
From the Department of Physiology, University of Wisconsin School of Medicine and Public Health, Madison.
* To whom correspondence should be addressed. E-mail: stelzer{at}physiology.wisc.edu.
The heart is remarkably adaptable in its ability to vary its function to meet the changing demands of the circulatory system. During times of physiological stress, cardiac output increases in response to increased sympathetic activity, which results in protein kinase A (PKA)-mediated phosphorylations of the myofilament proteins cardiac troponin (cTn)I and cardiac myosin-binding protein (cMyBP)-C. Despite the importance of this mechanism, little is known about the relative contributions of cTnI and cMyBP-C phosphorylation to increased cardiac contractility. Using engineered mouse lines either lacking cMyBP-C (cMyBP-C-/-) or expressing a non-PKA phosphorylatable cTnI (cTnIala2), or both (cMyBP-C-/-/cTnIala2), we investigated the roles of cTnI and cMyBP-C phosphorylation in the regulation of the stretch-activation response. PKA treatment of wild-type and cTnIala2 skinned ventricular myocardium accelerated stretch activation such that the response was indistinguishable from stretch activation of cMyBP-C-/- or cMyBP-C-/-/cTnIala2 myocardium; however, PKA had no effect on stretch activation in cMyBP-C-/- or cMyBP-C-/-/cTnIala2 myocardium. These results indicate that the acceleration of stretch activation in wild-type and cTnIala2 myocardium is caused by phosphorylation of cMyBP-C and not cTnI. We conclude that the primary effect of PKA phosphorylation of cTnI is reduced Ca2+ sensitivity of force, whereas phosphorylation of cMyBP-C accelerates the kinetics of force development. These results predict that PKA phosphorylation of myofibrillar proteins in living myocardium contributes to accelerated relaxation in diastole and increased rates of force development in systole.
Key words: cross-bridge kinetics •
-adrenergic agonists •
positive inotropy •
contractile protein function
This article has been cited by other articles:
 |
|
 |
|
  Y. Ge, I. N. Rybakova, Q. Xu, and R. L. Moss Top-down high-resolution mass spectrometry of cardiac myosin binding protein C revealed that truncation alters protein phosphorylation state PNAS, August 4, 2009; 106(31): 12658 - 12663. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Hamdani, W. J. Paulus, L. van Heerebeek, A. Borbely, N. M. Boontje, M. J. Zuidwijk, J. G.F. Bronzwaer, W. S. Simonides, H. W. M. Niessen, G. J. M. Stienen, et al. Distinct myocardial effects of beta-blocker therapy in heart failure with normal and reduced left ventricular ejection fraction Eur. Heart J., August 1, 2009; 30(15): 1863 - 1872. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Matsuba, T. Terui, J. O-Uchi, H. Tanaka, T. Ojima, I. Ohtsuki, S. Ishiwata, S. Kurihara, and N. Fukuda Protein kinase A-dependent modulation of Ca2+ sensitivity in cardiac and fast skeletal muscles after reconstitution with cardiac troponin J. Gen. Physiol., June 1, 2009; 133(6): 571 - 581. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. F. Shaffer, R. W. Kensler, and S. P. Harris The Myosin-binding Protein C Motif Binds to F-actin in a Phosphorylation-sensitive Manner J. Biol. Chem., May 1, 2009; 284(18): 12318 - 12327. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Hanft and K. S. McDonald Sarcomere length dependence of power output is increased after PKA treatment in rat cardiac myocytes Am J Physiol Heart Circ Physiol, May 1, 2009; 296(5): H1524 - H1531. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. van Dijk, D. Dooijes, C. dos Remedios, M. Michels, J. M.J. Lamers, S. Winegrad, S. Schlossarek, L. Carrier, F. J. ten Cate, G. J.M. Stienen, et al. Cardiac Myosin-Binding Protein C Mutations and Hypertrophic Cardiomyopathy: Haploinsufficiency, Deranged Phosphorylation, and Cardiomyocyte Dysfunction Circulation, March 24, 2009; 119(11): 1473 - 1483. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Sadayappan, J. Gulick, R. Klevitsky, J. N. Lorenz, M. Sargent, J. D. Molkentin, and J. Robbins Cardiac Myosin Binding Protein-C Phosphorylation in a {beta}-Myosin Heavy Chain Background Circulation, March 10, 2009; 119(9): 1253 - 1262. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. B. Scruggs, A. C. Hinken, A. Thawornkaiwong, J. Robbins, L. A. Walker, P. P. de Tombe, D. L. Geenen, P. M. Buttrick, and R. J. Solaro Ablation of Ventricular Myosin Regulatory Light Chain Phosphorylation in Mice Causes Cardiac Dysfunction in Situ and Affects Neighboring Myofilament Protein Phosphorylation J. Biol. Chem., February 20, 2009; 284(8): 5097 - 5106. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. W. Tong, J. E. Stelzer, M. L. Greaser, P. A. Powers, and R. L. Moss Acceleration of Crossbridge Kinetics by Protein Kinase A Phosphorylation of Cardiac Myosin Binding Protein C Modulates Cardiac Function Circ. Res., October 24, 2008; 103(9): 974 - 982. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Solaro Multiplex Kinase Signaling Modifies Cardiac Function at the Level of Sarcomeric Proteins J. Biol. Chem., October 3, 2008; 283(40): 26829 - 26833. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Davis, M. V. Westfall, D. Townsend, M. Blankinship, T. J. Herron, G. Guerrero-Serna, W. Wang, E. Devaney, and J. M. Metzger Designing Heart Performance by Gene Transfer Physiol Rev, October 1, 2008; 88(4): 1567 - 1651. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. A. Colson, T. Bekyarova, M. R. Locher, D. P. Fitzsimons, T. C. Irving, and R. L. Moss Protein Kinase A-Mediated Phosphorylation of cMyBP-C Increases Proximity of Myosin Heads to Actin in Resting Myocardium Circ. Res., August 1, 2008; 103(3): 244 - 251. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-H. Yeh, R. Wakili, X.-Y. Qi, D. Chartier, P. Boknik, S. Kaab, U. Ravens, P. Coutu, D. Dobrev, and S. Nattel Calcium-Handling Abnormalities Underlying Atrial Arrhythmogenesis and Contractile Dysfunction in Dogs With Congestive Heart Failure Circ Arrhythm Electrophysiol, June 1, 2008; 1(2): 93 - 102. [Abstract] [Full Text] [PDF]
|
|