Published online before print August 29, 2002, doi: 10.1161/01.RES.0000035246.27856.53
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on May 9, 2002
Revised on August 1, 2002
Accepted on August 16, 2002
p21-Activated Kinase Increases the Calcium Sensitivity of Rat Triton-Skinned Cardiac Muscle Fiber Bundles via a Mechanism Potentially Involving Novel Phosphorylation of Troponin I
Nina Buscemi ;
From the Departments of Physiology (N.B., I.N., J.E.V.E.) and Biochemistry (D.B.F., J.E.V.E.), Queen's University, Kingston, Ontario, Canada.
* To whom correspondence should be addressed. E-mail: JVE1{at}post.queensu.ca.
Phosphorylation of myofilament proteins by kinases such as cAMP-dependent protein kinase and protein kinase C has been shown to lead to altered thin-filament protein-protein interactions and modulation of cardiac function in vitro. In the present study, we report that a small GTPase-dependent kinase, p21-activated kinase (PAK), increases the calcium sensitivity of Triton-skinned cardiac muscle fiber bundles. Constitutively active PAK3 caused an average 1.25-fold (25.0±6.0%, n=6) increase in force at pCa 5.75, 1.44-fold (44.0±7.78%, n=6) at pCa 6.25, and 2.41-fold (141.2±23.7%, n=4) at pCa 6.5, representing a change in pCa50 value of approximately 0.25 U. Constitutively active PAK3 produced no change in force under conditions of relaxation (pCa 8.0) or maximal contraction (pCa 4.5). Furthermore, an inactive, kinase-dead form of PAK3 failed to produce any change in force development at any pCa value. The myofilament proteins phosphorylated by PAK3, at pCa 6.5, are desmin, troponin T, troponin I, and an unidentified 70-kDa protein. Importantly, cardiac troponin I was found to be phosphorylated at serine 149 of human cardiac troponin I, representing a novel phosphorylation site. These findings suggest a novel mechanism of modulating the calcium sensitivity of cardiac muscle contraction.
Key words: p21-activated kinase • calcium • cardiac • troponin I • phosphorylation
This article has been cited by other articles:
 |
|
 |
|
  G. A. Ramirez-Correa, W. Jin, Z. Wang, X. Zhong, W. D. Gao, W. B. Dias, C. Vecoli, G. W. Hart, and A. M. Murphy O-Linked GlcNAc Modification of Cardiac Myofilament Proteins: A Novel Regulator of Myocardial Contractile Function Circ. Res., December 5, 2008; 103(12): 1354 - 1358. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Zabrouskov, Y. Ge, J. Schwartz, and J. W. Walker Unraveling Molecular Complexity of Phosphorylated Human Cardiac Troponin I by Top Down Electron Capture Dissociation/Electron Transfer Dissociation Mass Spectrometry Mol. Cell. Proteomics, October 1, 2008; 7(10): 1838 - 1849. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Hamdani, V. Kooij, S. van Dijk, D. Merkus, W. J. Paulus, C. d. Remedios, D. J. Duncker, G. J.M. Stienen, and J. van der Velden Sarcomeric dysfunction in heart failure Cardiovasc Res, March 1, 2008; 77(4): 649 - 658. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. A. Sheehan, Y. Ke, and R. J. Solaro p21-Activated kinase-1 and its role in integrated regulation of cardiac contractility Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2007; 293(3): R963 - R973. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Brown, D. P. Del Re, and M. A. Sussman The Rac and Rho Hall of Fame: A Decade of Hypertrophic Signaling Hits Circ. Res., March 31, 2006; 98(6): 730 - 742. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Layland, R. J. Solaro, and A. M. Shah Regulation of cardiac contractile function by troponin I phosphorylation Cardiovasc Res, April 1, 2005; 66(1): 12 - 21. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M. Murphy Another New Kinase Targets Troponin I Circ. Res., November 26, 2004; 95(11): 1043 - 1045. [Full Text] [PDF]
|
|
|
|
|
|
R. S. Haworth, F. Cuello, T. J. Herron, G. Franzen, J. C. Kentish, M. Gautel, and M. Avkiran Protein Kinase D Is a Novel Mediator of Cardiac Troponin I Phosphorylation and Regulates Myofilament Function Circ. Res., November 26, 2004; 95(11): 1091 - 1099. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.E. Van Eyk Lessons From Old and New Kinases Circ. Res., February 6, 2004; 94(2): 135 - 137. [Full Text] [PDF]
|
|
|
|
|
|
J. M. Metzger and M. V. Westfall Covalent and Noncovalent Modification of Thin Filament Action: The Essential Role of Troponin in Cardiac Muscle Regulation Circ. Res., February 6, 2004; 94(2): 146 - 158. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Ke, L. Wang, W. G. Pyle, P. P. de Tombe, and R. J. Solaro Intracellular Localization and Functional Effects of P21-Activated Kinase-1 (Pak1) in Cardiac Myocytes Circ. Res., February 6, 2004; 94(2): 194 - 200. [Abstract] [Full Text] [PDF]
|
|