Published online before print January 15, 2004, doi: 10.1161/01.RES.0000117307.57798.F5
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2004 American Heart Association, Inc.
Cellular Biology |
Frequency- and Afterload-Dependent Cardiac Modulation In Vivo by Troponin I With Constitutively Active Protein Kinase A Phosphorylation Sites
From the Departments of Pediatrics (D.G.S., L.B.S., A.M.M.) and Medicine (E.T., P.M.L.J., D.A.K.), Johns Hopkins University School of Medicine, Baltimore, Md.
Correspondence to Anne M. Murphy, Ross 1144, Johns Hopkins University School of Medicine, 720 Rutland Ave, Baltimore, MD 21205. E-mail murphy{at}jhmi.edu
Acute ß-adrenergic stimulation enhances cardiac contractility, accelerates muscle relaxation, and amplifies the inotropic and lusitropic response to increased stimulation frequency. These effects are modulated by phosphorylation of calcium handling and myofilament proteins such as troponin I (TnI) by protein kinase A (PKA). To more directly delineate the role of TnI PKA phosphorylation, transgenic mice were generated that overexpress cardiac TnI in which the serine residues normally targeted by PKA are mutated to aspartic acid to mimic constitutive phosphorylation (TnIDD22,23). Native cardiac TnI was near completely replaced in one transgenic line as assessed by in vitro phosphorylation, and this led to reduced calcium sensitivity of myofibrillar MgATPase, as expected. TnIDD22,23 mice had mildly enhanced basal systolic and diastolic function, and displayed marked augmentation of frequency-dependent inotropy and relaxation, with a peak frequency response 2-fold greater in mutants than controls (P<0.005). Increasing afterload prolonged relaxation more in nontransgenic than TnIDD22,23 (P<0.02), whereas contractile responses to afterload were similar between these strains. Isoproterenol treatment eliminated the differential force-frequency and afterload response between TnIDD22,23 and controls. In contrast to in vivo studies, isolated isometric trabeculae from nontransgenic and TnIDD22,23 mice had similar basal, isoproterenol-, and frequency-stimulated function, suggesting that muscle shortening may be important to TnI PKA effects. These results support a novel role for cardiac TnI PKA phosphorylation in the rate-dependent enhancement of systolic and diastolic function in vivo and afterload sensitivity of relaxation. These results have implications for cardiac failure in which force-frequency modulation is blunted and afterload relaxation sensitivity increased in association with diminished PKA TnI phosphorylation.
Key Words: troponin I • protein kinase A • cardiac function • myofilament
This article has been cited by other articles:
 |
|
 |
|
  N. C. Lai, T. Tang, M. H. Gao, M. Saito, T. Takahashi, D. M. Roth, and H. K. Hammond Activation of Cardiac Adenylyl Cyclase Expression Increases Function of the Failing Ischemic Heart in Mice J. Am. Coll. Cardiol., April 15, 2008; 51(15): 1490 - 1497. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Sadayappan, N. Finley, J. W. Howarth, H. Osinska, R. Klevitsky, J. N. Lorenz, P. R. Rosevear, and J. Robbins Role of the acidic N' region of cardiac troponin I in regulating myocardial function FASEB J, April 1, 2008; 22(4): 1246 - 1257. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Avkiran, A. J. Rowland, F. Cuello, and R. S. Haworth Protein Kinase D in the Cardiovascular System: Emerging Roles in Health and Disease Circ. Res., February 1, 2008; 102(2): 157 - 163. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Nagayama, E. Takimoto, S. Sadayappan, J. O. Mudd, J.G. Seidman, J. Robbins, and D. A. Kass Control of In Vivo Contraction/Relaxation Kinetics by Myosin Binding Protein C: Protein Kinase A Phosphorylation Dependent and Independent Regulation Circulation, November 20, 2007; 116(21): 2399 - 2408. [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. E. Stelzer, J. R. Patel, J. W. Walker, and R. L. Moss Differential Roles of Cardiac Myosin-Binding Protein C and Cardiac Troponin I in the Myofibrillar Force Responses to Protein Kinase A Phosphorylation Circ. Res., August 31, 2007; 101(5): 503 - 511. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. A. Ramirez-Correa and A. M. Murphy Is Phospholamban or Troponin I the "Prima Donna" in -Adrenergic Induced Lusitropy? Circ. Res., August 17, 2007; 101(4): 326 - 327. [Full Text] [PDF]
|
|
|
|
|
|
S.-i. Yasuda, P. Coutu, S. Sadayappan, J. Robbins, and J. M. Metzger Cardiac Transgenic and Gene Transfer Strategies Converge to Support an Important Role for Troponin I in Regulating Relaxation in Cardiac Myocytes Circ. Res., August 17, 2007; 101(4): 377 - 386. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. R. Lamberts, N. Hamdani, T. W. Soekhoe, N. M. Boontje, R. Zaremba, L. A. Walker, P. P. de Tombe, J. van der Velden, and G. J. M. Stienen Frequency-dependent myofilament Ca2+ desensitization in failing rat myocardium J. Physiol., July 15, 2007; 582(2): 695 - 709. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. J. Biesiadecki, T. Kobayashi, J. S. Walker, R. John Solaro, and P. P. de Tombe The Troponin C G159D Mutation Blunts Myofilament Desensitization Induced by Troponin I Ser23/24 Phosphorylation Circ. Res., May 25, 2007; 100(10): 1486 - 1493. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. D. Varian and P. M. L. Janssen Frequency-dependent acceleration of relaxation involves decreased myofilament calcium sensitivity Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2212 - H2219. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C. Hinken and R. J. Solaro A Dominant Role of Cardiac Molecular Motors in the Intrinsic Regulation of Ventricular Ejection and Relaxation Physiology, April 1, 2007; 22(2): 73 - 80. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Cuello, S. C. Bardswell, R. S. Haworth, X. Yin, S. Lutz, T. Wieland, M. Mayr, J. C. Kentish, and M. Avkiran Protein Kinase D Selectively Targets Cardiac Troponin I and Regulates Myofilament Ca2+ Sensitivity in Ventricular Myocytes Circ. Res., March 30, 2007; 100(6): 864 - 873. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Ballo, A. Bocelli, and S. Mondillo Adaptive and Maladaptive Cardiac Hypertrophy: What Is the Effective Role of Heat Shock Transcription Factor 1? Circ. Res., February 16, 2007; 100(3): e45 - e46. [Full Text] [PDF]
|
|
|
|
|
|
K. C. Bilchick, J. G. Duncan, R. Ravi, E. Takimoto, H. C. Champion, W. D. Gao, L. B. Stull, D. A. Kass, and A. M. Murphy Heart failure-associated alterations in troponin I phosphorylation impair ventricular relaxation-afterload and force-frequency responses and systolic function Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H318 - H325. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. A. Narolska, N. Piroddi, A. Belus, N. M. Boontje, B. Scellini, S. Deppermann, R. Zaremba, R. J. Musters, C. dos Remedios, K. Jaquet, et al. Impaired Diastolic Function After Exchange of Endogenous Troponin I With C-Terminal Truncated Troponin I in Human Cardiac Muscle Circ. Res., October 27, 2006; 99(9): 1012 - 1020. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Niederer, P. J. Hunter, and N. P. Smith A Quantitative Analysis of Cardiac Myocyte Relaxation: A Simulation Study Biophys. J., March 1, 2006; 90(5): 1697 - 1722. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Kass Cardiac Resynchronization Therapy and Cardiac Reserve: How You Climb a Staircase May Alter Its Steepness Circulation, February 21, 2006; 113(7): 923 - 925. [Full Text] [PDF]
|
|
|
|
 |
|
 M. V. Westfall, A. M. Lee, and D. A. Robinson Differential Contribution of Troponin I Phosphorylation Sites to the Endothelin-modulated Contractile Response J. Biol. Chem., December 16, 2005; 280(50): 41324 - 41331. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. M. L. Janssen, N. Hiranandani, T. A. Mays, and J. A. Rafael-Fortney Utrophin deficiency worsens cardiac contractile dysfunction present in dystrophin-deficient mdx mice Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2373 - H2378. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Itoh, B. Ding, C. P. Bains, N. Wang, Y. Takeishi, T. Jalili, G. L. King, R. A. Walsh, C. Yan, and J.-i. Abe Role of p90 Ribosomal S6 Kinase (p90RSK) in Reactive Oxygen Species and Protein Kinase C {beta} (PKC-{beta})-mediated Cardiac Troponin I Phosphorylation J. Biol. Chem., June 24, 2005; 280(25): 24135 - 24142. [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]
|
|
|
|
|
|
S. Sakthivel, N. L. Finley, P. R. Rosevear, J. N. Lorenz, J. Gulick, S. Kim, P. VanBuren, L. A. Martin, and J. Robbins In Vivo and in Vitro Analysis of Cardiac Troponin I Phosphorylation J. Biol. Chem., January 7, 2005; 280(1): 703 - 714. [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]
|
|
|
|
|
|
C. W. Tong, R. D. Gaffin, D. C. Zawieja, and M. Muthuchamy Roles of phosphorylation of myosin binding protein-C and troponin I in mouse cardiac muscle twitch dynamics J. Physiol., August 1, 2004; 558(3): 927 - 941. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Kass, J. G.F. Bronzwaer, and W. J. Paulus What Mechanisms Underlie Diastolic Dysfunction in Heart Failure? Circ. Res., June 25, 2004; 94(12): 1533 - 1542. [Abstract] [Full Text] [PDF]
|
|