Circulation Research. 2002;90:1181-1188
Published online before print May 9, 2002, doi: 10.1161/01.RES.0000021115.24712.99
Published online before print May 9, 2002, doi: 10.1161/01.RES.0000021115.24712.99
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2002 American Heart Association, Inc.
Cellular Biology |
Protein Kinase A Phosphorylates Titin’s Cardiac-Specific N2B Domain and Reduces Passive Tension in Rat Cardiac Myocytes
From the Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology (R.Y., Y.W., M.M., H.G.), Washington State University, Pullman; Muscle Biology Laboratory (M.G.), University of Wisconsin, Madison; and Anästhesiologie und Operative Intensivmedizin (S.L.), Universitätsklinikum Mannheim, Mannheim, Germany.
Correspondence to Dr H. Granzier, Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Wegner Hall, 205, Washington State University, Pullman, WA 99164-6520. E-mail granzier{at}wsunix.wsu.edu
Abstract— ß-Adrenergic stimulation of cardiac muscle activates protein kinase A (PKA), which is known to phosphorylate proteins on the thin and thick filaments of the sarcomere. Cardiac muscle sarcomeres contain a third filament system composed of titin, and here we demonstrate that titin is also phosphorylated by the ß-adrenergic pathway. Titin phosphorylation was observed after ß-receptor stimulation of intact cardiac myocytes and incubation of skinned cardiac myocytes with PKA. Mechanical experiments with isolated myocytes revealed that PKA significantly reduces passive tension. In vitro phosphorylation of recombinant titin fragments and immunoelectron microscopy suggest that PKA targets a subdomain of the elastic segment of titin, referred to as the N2B spring element. The N2B spring element is expressed only in cardiac titins, in which it plays an important role in determining the level of passive tension. Because titin-based passive tension is a determinant of diastolic function, these results suggest that titin phosphorylation may modulate cardiac function in vivo.
Key Words: connectin • diastole • myocyte mechanics • ß-adrenergic signaling • resting tension
This article has been cited by other articles:
 |
|
 |
|
  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., May 25, 2009; 133(6): 571 - 581. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Zhu, J. Bogomolovas, S. Labeit, and H. Granzier Single Molecule Force Spectroscopy of the Cardiac Titin N2B Element: EFFECTS OF THE MOLECULAR CHAPERONE {alpha}B-CRYSTALLIN WITH DISEASE-CAUSING MUTATIONS J. Biol. Chem., May 15, 2009; 284(20): 13914 - 13923. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Duncker, N. M. Boontje, D. Merkus, A. Versteilen, J. Krysiak, G. Mearini, A. El-Armouche, V. J. de Beer, J. M.J. Lamers, L. Carrier, et al. Prevention of Myofilament Dysfunction by {beta}-Blocker Therapy in Postinfarct Remodeling Circ Heart Fail, May 1, 2009; 2(3): 233 - 242. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Borbely, I. Falcao-Pires, L. van Heerebeek, N. Hamdani, I. Edes, C. Gavina, A. F. Leite-Moreira, J. G.F. Bronzwaer, Z. Papp, J. van der Velden, et al. Hypophosphorylation of the Stiff N2B Titin Isoform Raises Cardiomyocyte Resting Tension in Failing Human Myocardium Circ. Res., March 27, 2009; 104(6): 780 - 786. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Borbely, L. van Heerebeek, and W. J. Paulus Transcriptional and Posttranslational Modifications of Titin: Implications for Diastole Circ. Res., January 2, 2009; 104(1): 12 - 14. [Full Text] [PDF]
|
|
|
|
|
|
M. Kruger, S. Kotter, A. Grutzner, P. Lang, C. Andresen, M. M. Redfield, E. Butt, C. G. dos Remedios, and W. A. Linke Protein Kinase G Modulates Human Myocardial Passive Stiffness by Phosphorylation of the Titin Springs Circ. Res., January 2, 2009; 104(1): 87 - 94. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. A. Linke Sense and stretchability: The role of titin and titin-associated proteins in myocardial stress-sensing and mechanical dysfunction Cardiovasc Res, March 1, 2008; 77(4): 637 - 648. [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]
|
|
|
|
|
|
V. Bito, J. van der Velden, P. Claus, C. Dommke, A. Van Lommel, L. Mortelmans, E. Verbeken, B. Bijnens, G. Stienen, and K. R. Sipido Reduced Force Generating Capacity in Myocytes From Chronically Ischemic, Hibernating Myocardium Circ. Res., February 2, 2007; 100(2): 229 - 237. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. D. Buckberg, M. Castella, M. Gharib, and S. Saleh Structure/function interface with sequential shortening of basal and apical components of the myocardial band Eur. J. Cardiothorac. Surg., April 1, 2006; 29(Suppl_1): S75 - S97. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. D. Buckberg, M. Castella, M. Gharib, and S. Saleh Active myocyte shortening during the 'isovolumetric relaxation' phase of diastole is responsible for ventricular suction; 'systolic ventricular filling' Eur. J. Cardiothorac. Surg., April 1, 2006; 29(Suppl_1): S98 - S106. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Castella, G. D. Buckberg, and S. Saleh Diastolic dysfunction in stunned myocardium: a state of abnormal excitation-contraction coupling that is limited by Na+-H+ exchange inhibition Eur. J. Cardiothorac. Surg., April 1, 2006; 29(Suppl_1): S107 - S114. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kogler The role of cardiac myosin binding protein-C as a regulator of myofilament Ca2+ sensitivity Cardiovasc Res, February 1, 2006; 69(2): 304 - 306. [Full Text] [PDF]
|
|
|
|
|
|
O. Cazorla, S. Szilagyi, N. Vignier, G. Salazar, E. Kramer, G. Vassort, L. Carrier, and A. Lacampagne Length and protein kinase A modulations of myocytes in cardiac myosin binding protein C-deficient mice Cardiovasc Res, February 1, 2006; 69(2): 370 - 380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Castella, G. D. Buckberg, S. Saleh, and M. Gharib Structure function interface with sequential shortening of basal and apical components of the myocardial band Eur. J. Cardiothorac. Surg., June 1, 2005; 27(6): 980 - 987. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Kirton, A. J. Taberner, P. M. F. Nielsen, A. A. Young, and D. S. Loiselle Effects of BDM, [Ca2+]o, and temperature on the dynamic stiffness of quiescent cardiac trabeculae from rat Am J Physiol Heart Circ Physiol, April 1, 2005; 288(4): H1662 - H1667. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. C. Lim and D. B. Sawyer Modulation of Cardiac Function: Titin Springs into Action J. Gen. Physiol., February 28, 2005; 125(3): 249 - 252. [Full Text] [PDF]
|
|
|
|
|
|
N. Fukuda, Y. Wu, P. Nair, and H. L. Granzier Phosphorylation of Titin Modulates Passive Stiffness of Cardiac Muscle in a Titin Isoform-dependent Manner J. Gen. Physiol., February 28, 2005; 125(3): 257 - 271. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Borbely, J. van der Velden, Z. Papp, J. G.F. Bronzwaer, I. Edes, G. J.M. Stienen, and W. J. Paulus Cardiomyocyte Stiffness in Diastolic Heart Failure Circulation, February 15, 2005; 111(6): 774 - 781. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Fujita, D. Labeit, B. Gerull, S. Labeit, and H. L. Granzier Titin isoform-dependent effect of calcium on passive myocardial tension Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2528 - H2534. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. LeWinter Titin Isoforms in Heart Failure: Are There Benefits to Supersizing? Circulation, July 13, 2004; 110(2): 109 - 111. [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]
|
|
|
|
|
|
J. R Pena and B. M Wolska Troponin I phosphorylation plays an important role in the relaxant effect of {beta}-adrenergic stimulation in mouse hearts Cardiovasc Res, March 1, 2004; 61(4): 756 - 763. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Bullard, C. Ferguson, A. Minajeva, M. C. Leake, M. Gautel, D. Labeit, L. Ding, S. Labeit, J. Horwitz, K. R. Leonard, et al. Association of the Chaperone {alpha}B-crystallin with Titin in Heart Muscle J. Biol. Chem., February 27, 2004; 279(9): 7917 - 7924. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. L. Granzier and S. Labeit The Giant Protein Titin: A Major Player in Myocardial Mechanics, Signaling, and Disease Circ. Res., February 20, 2004; 94(3): 284 - 295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. G. Pyle and R. J. Solaro At the Crossroads of Myocardial Signaling: The Role of Z-Discs in Intracellular Signaling and Cardiac Function Circ. Res., February 20, 2004; 94(3): 296 - 305. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. A. Barash, L. Mathew, A. F. Ryan, J. Chen, and R. L. Lieber Rapid muscle-specific gene expression changes after a single bout of eccentric contractions in the mouse Am J Physiol Cell Physiol, February 1, 2004; 286(2): C355 - C364. [Abstract] [Full Text]
|
|
|
|
|
|
C. M. Warren, M. C. Jordan, K. P. Roos, P. R. Krzesinski, and M. L. Greaser Titin isoform expression in normal and hypertensive myocardium Cardiovasc Res, July 1, 2003; 59(1): 86 - 94. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. P Konhilas, T. C Irving, B. M Wolska, E. E Jweied, A. F Martin, R John Solaro, and P. P de Tombe Troponin I in the murine myocardium: influence on length-dependent activation and interfilament spacing J. Physiol., March 15, 2003; 547(3): 951 - 961. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Layland and J. C Kentish Myofilament-based relaxant effect of isoprenaline revealed during work-loop contractions in rat cardiac trabeculae J. Physiol., October 1, 2002; 544(1): 171 - 182. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Hein, W. H. Gaasch, and J. Schaper Giant Molecule Titin and Myocardial Stiffness Circulation, September 10, 2002; 106(11): 1302 - 1304. [Full Text] [PDF]
|
|