Published online before print December 15, 2005, doi: 10.1161/01.RES.0000200178.34179.93
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© 2006 American Heart Association, Inc.
Cellular Biology |
Compartmentalized Phosphodiesterase-2 Activity Blunts ß-Adrenergic Cardiac Inotropy via an NO/cGMP-Dependent Pathway
From the Dulbecco Telethon Institute (M.M., A.T., V.L., M.Z.) and Venetian Institute of Molecular Medicine (M.M., A.T., V.L., T.P., M.Z.), Padova, Italy; Department of Cardiology (C.G.T., D.A.K., N.P.), Johns Hopkins Medical Institutions, Baltimore, Md; Division of Biochemistry and Molecular Biology (Y.-F.C., M.D.H.), Institute of Biomedical and Life Sciences, University of Glasgow, Scotland, United Kingdom; Department of Pharmacology (W.R.D.), University of Vermont, Burlington; and Department of Biomedical Sciences (T.P.), University of Padova, Italy.
Correspondence to Dr Manuela Zaccolo, Venetian Institute for Molecular Medicine, Room G210, Via Orus 2, Padova 35129, Italy. E-mail manuela.zaccolo{at}unipd.it
ß-Adrenergic signaling via cAMP generation and PKA activation mediates the positive inotropic effect of catecholamines on heart cells. Given the large diversity of protein kinase A targets within cardiac cells, a precisely regulated and confined activity of such signaling pathway is essential for specificity of response. Phosphodiesterases (PDEs) are the only route for degrading cAMP and are thus poised to regulate intracellular cAMP gradients. Their spatial confinement to discrete compartments and functional coupling to individual receptors provides an efficient way to control local [cAMP]i in a stimulus-specific manner. By performing real-time imaging of cyclic nucleotides in living ventriculocytes we identify a prominent role of PDE2 in selectively shaping the cAMP response to catecholamines via a pathway involving ß3-adrenergic receptors, NO generation and cGMP production. In cardiac myocytes, PDE2, being tightly coupled to the pool of adenylyl cyclases activated by ß-adrenergic receptor stimulation, coordinates cGMP and cAMP signaling in a novel feedback control loop of the ß-adrenergic pathway. In this, activation of ß3-adrenergic receptors counteracts cAMP generation obtained via stimulation of ß1/ß2-adrenoceptors. Our study illustrates the key role of compartmentalized PDE2 in the control of catecholamine-generated cAMP and furthers our understanding of localized cAMP signaling.
Key Words: PDE2 • cAMP • cardiomyocytes • fluorescence resonance energy transfer • compartmentalization
This article has been cited by other articles:
 |
|
 |
|
  T. M. A. Mohamed, D. Oceandy, S. Prehar, N. Alatwi, Z. Hegab, F. M. Baudoin, A. Pickard, A. O. Zaki, R. Nadif, E. J. Cartwright, et al. Specific Role of Neuronal Nitric-oxide Synthase when Tethered to the Plasma Membrane Calcium Pump in Regulating the {beta}-Adrenergic Signal in the Myocardium J. Biol. Chem., May 1, 2009; 284(18): 12091 - 12098. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. P. Adderley, E. A. Dufaux, M. Sridharan, E. A. Bowles, M. S. Hanson, A. H. Stephenson, M. L. Ellsworth, and R. S. Sprague Iloprost- and isoproterenol-induced increases in cAMP are regulated by different phosphodiesterases in erythrocytes of both rabbits and humans Am J Physiol Heart Circ Physiol, May 1, 2009; 296(5): H1617 - H1624. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Rozec, M. Erfanian, K. Laurent, J.-N. Trochu, and C. Gauthier Nebivolol, a vasodilating selective beta(1)-blocker, is a beta(3)-adrenoceptor agonist in the nonfailing transplanted human heart. J. Am. Coll. Cardiol., April 28, 2009; 53(17): 1532 - 1538. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Pokreisz, S. Vandenwijngaert, V. Bito, A. Van den Bergh, I. Lenaerts, C. Busch, G. Marsboom, O. Gheysens, P. Vermeersch, L. Biesmans, et al. Ventricular Phosphodiesterase-5 Expression Is Increased in Patients With Advanced Heart Failure and Contributes to Adverse Ventricular Remodeling After Myocardial Infarction in Mice Circulation, January 27, 2009; 119(3): 408 - 416. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. C. Tovey, S. G. Dedos, E. J.A. Taylor, J. E. Church, and C. W. Taylor Selective coupling of type 6 adenylyl cyclase with type 2 IP3 receptors mediates direct sensitization of IP3 receptors by cAMP J. Cell Biol., October 20, 2008; 183(2): 297 - 311. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. R. Ares, P. Caceres, F. J. Alvarez-Leefmans, and P. A. Ortiz cGMP decreases surface NKCC2 levels in the thick ascending limb: role of phosphodiesterase 2 (PDE2) Am J Physiol Renal Physiol, October 1, 2008; 295(4): F877 - F887. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Kass Message Delivered: How Myocytes Control cAMP Signaling Circ. Res., May 9, 2008; 102(9): 1002 - 1004. [Full Text] [PDF]
|
|
|
|
 |
|
 L. W. M. Nausch, J. Ledoux, A. D. Bonev, M. T. Nelson, and W. R. Dostmann Differential patterning of cGMP in vascular smooth muscle cells revealed by single GFP-linked biosensors PNAS, January 8, 2008; 105(1): 365 - 370. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Kass, H. C. Champion, and J. A. Beavo Phosphodiesterase Type 5: Expanding Roles in Cardiovascular Regulation Circ. Res., November 26, 2007; 101(11): 1084 - 1095. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Vandeput, S. L. Wolda, J. Krall, R. Hambleton, L. Uher, K. N. McCaw, P. B. Radwanski, V. Florio, and M. A. Movsesian Cyclic Nucleotide Phosphodiesterase PDE1C1 in Human Cardiac Myocytes J. Biol. Chem., November 9, 2007; 282(45): 32749 - 32757. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. H. Huxley, J. J. Wang, and I. H. Sarelius Adaptation of coronary microvascular exchange in arterioles and venules to exercise training and a role for sex in determining permeability responses Am J Physiol Heart Circ Physiol, August 1, 2007; 293(2): H1196 - H1205. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Kass, E. Takimoto, T. Nagayama, and H. C. Champion Phosphodiesterase regulation of nitric oxide signaling Cardiovasc Res, July 15, 2007; 75(2): 303 - 314. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Schmid, Z. Sutto, M.-C. Nlend, G. Horvath, N. Schmid, J. Buck, L. R. Levin, G. E. Conner, N. Fregien, and M. Salathe Soluble Adenylyl Cyclase Is Localized to Cilia and Contributes to Ciliary Beat Frequency Regulation via Production of cAMP J. Gen. Physiol., July 1, 2007; 130(1): 99 - 109. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Zaccolo and M. A. Movsesian cAMP and cGMP Signaling Cross-Talk: Role of Phosphodiesterases and Implications for Cardiac Pathophysiology Circ. Res., June 8, 2007; 100(11): 1569 - 1578. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. K. de Oliveira, M. Hoffmeister, S. Gambaryan, W. Muller-Esterl, J. A. Guimaraes, and A. P. Smolenski Phosphodiesterase 2A Forms a Complex with the Co-chaperone XAP2 and Regulates Nuclear Translocation of the Aryl Hydrocarbon Receptor J. Biol. Chem., May 4, 2007; 282(18): 13656 - 13663. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Takimoto, D. Belardi, C. G. Tocchetti, S. Vahebi, G. Cormaci, E. A. Ketner, A. L. Moens, H. C. Champion, and D. A. Kass Compartmentalization of Cardiac {beta}-Adrenergic Inotropy Modulation by Phosphodiesterase Type 5 Circulation, April 24, 2007; 115(16): 2159 - 2167. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. D. Houslay, G. S. Baillie, and D. H. Maurice cAMP-Specific Phosphodiesterase-4 Enzymes in the Cardiovascular System: A Molecular Toolbox for Generating Compartmentalized cAMP Signaling Circ. Res., April 13, 2007; 100(7): 950 - 966. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Yan, C. L. Miller, and J.-i. Abe Regulation of Phosphodiesterase 3 and Inducible cAMP Early Repressor in the Heart Circ. Res., March 2, 2007; 100(4): 489 - 501. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Oberholzer, G. Marti, M. Baresic, S. Kunz, A. Hemphill, and T. Seebeck The Trypanosoma brucei cAMP phosphodiesterases TbrPDEB1 and TbrPDEB2: flagellar enzymes that are essential for parasite virulence FASEB J, March 1, 2007; 21(3): 720 - 731. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Omori and J. Kotera Overview of PDEs and Their Regulation Circ. Res., February 16, 2007; 100(3): 309 - 327. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. G. Tocchetti, W. Wang, J. P. Froehlich, S. Huke, M. A. Aon, G. M. Wilson, G. Di Benedetto, B. O'Rourke, W. D. Gao, D. A. Wink, et al. Nitroxyl Improves Cellular Heart Function by Directly Enhancing Cardiac Sarcoplasmic Reticulum Ca2+ Cycling Circ. Res., January 5, 2007; 100(1): 96 - 104. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Cheng and J. P. Grande Cyclic Nucleotide Phosphodiesterase (PDE) Inhibitors: Novel Therapeutic Agents for Progressive Renal Disease Experimental Biology and Medicine, January 1, 2007; 232(1): 38 - 51. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. O. Nikolaev, M. Bunemann, E. Schmitteckert, M. J. Lohse, and S. Engelhardt Cyclic AMP Imaging in Adult Cardiac Myocytes Reveals Far-Reaching {beta}1-Adrenergic but Locally Confined {beta}2-Adrenergic Receptor-Mediated Signaling Circ. Res., November 10, 2006; 99(10): 1084 - 1091. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Terrin, G. Di Benedetto, V. Pertegato, Y.-F. Cheung, G. Baillie, M. J. Lynch, N. Elvassore, A. Prinz, F. W. Herberg, M. D. Houslay, et al. PGE1 stimulation of HEK293 cells generates multiple contiguous domains with different [cAMP]: role of compartmentalized phosphodiesterases J. Cell Biol., November 6, 2006; 175(3): 441 - 451. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Fischmeister, L. R.V. Castro, A. Abi-Gerges, F. Rochais, J. Jurevicius, J. Leroy, and G. Vandecasteele Compartmentation of Cyclic Nucleotide Signaling in the Heart: The Role of Cyclic Nucleotide Phosphodiesterases Circ. Res., October 13, 2006; 99(8): 816 - 828. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. T. Bender and J. A. Beavo Cyclic Nucleotide Phosphodiesterases: Molecular Regulation to Clinical Use Pharmacol. Rev., September 1, 2006; 58(3): 488 - 520. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Leineweber, M. Bohm, and G. Heusch Cyclic Adenosine Monophosphate in Acute Myocardial Infarction With Heart Failure: Slayer or Savior? Circulation, August 1, 2006; 114(5): 365 - 367. [Full Text] [PDF]
|
|
|
|
|
|
F. Rochais, A. Abi-Gerges, K. Horner, F. Lefebvre, D. M.F. Cooper, M. Conti, R. Fischmeister, and G. Vandecasteele A Specific Pattern of Phosphodiesterases Controls the cAMP Signals Generated by Different Gs-Coupled Receptors in Adult Rat Ventricular Myocytes Circ. Res., April 28, 2006; 98(8): 1081 - 1088. [Abstract] [Full Text] [PDF]
|
|