This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 98/8/1081    most recent 01.RES.0000218493.09370.8ev1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Rochais, F. Articles by Vandecasteele, G. Search for Related Content PubMed PubMed Citation Articles by Rochais, F. Articles by Vandecasteele, G. Related Collections Autonomic, reflex, and neurohumoral control of circulation Cell signalling/signal transduction Ion channels/membrane transport

(Circulation Research. 2006;98:1081.)
© 2006 American Heart Association, Inc.

Cellular Biology

A Specific Pattern of Phosphodiesterases Controls the cAMP Signals Generated by Different G_s-Coupled Receptors in Adult Rat Ventricular Myocytes

Francesca Rochais, Aniella Abi-Gerges, Kathleen Horner, Florence Lefebvre, Dermot M.F. Cooper, Marco Conti, Rodolphe Fischmeister, Grégoire Vandecasteele

From INSERM U769 (F.R., A.A.-G., F.L., R.F., G.V.), Châtenay-Malabry, France; Univ-Paris-Sud (F.R., A.A.-G., F.L., R.F., G.V.), U769 Faculté de Pharmacie, Châtenay-Malabry, France; Division of Reproductive Biology (K.H., M.C.), Department of Gynecology and Obstetrics, Stanford University, California; and Department of Pharmacology (D.M.F.C.), University of Cambridge, United Kingdom.

Correspondence to Dr Rodolphe Fischmeister, INSERM, U769, Université de Paris-Sud, Faculté de Pharmacie, 5, Rue J.-B. Clément, F-92296 Châtenay-Malabry Cedex, France. E-mail fisch{at}vjf.inserm.fr

Compartmentation of cAMP is thought to generate the specificity of G_s-coupled receptor action in cardiac myocytes, with phosphodiesterases (PDEs) playing a major role in this process by preventing cAMP diffusion. We tested this hypothesis in adult rat ventricular myocytes by characterizing PDEs involved in the regulation of cAMP signals and L-type Ca²⁺ current (I_Ca,L) on stimulation with ß₁-adrenergic receptors (ß₁-ARs), ß₂-ARs, glucagon receptors (Glu-Rs) and prostaglandin E₁ receptors (PGE₁-Rs). All receptors but PGE₁-R increased total cAMP, and inhibition of PDEs with 3-isobutyl-1-methylxanthine strongly potentiated these responses. When monitored in single cells by high-affinity cyclic nucleotide–gated (CNG) channels, stimulation of ß₁-AR and Glu-R increased cAMP, whereas ß₂-AR and PGE₁-R had no detectable effect. Selective inhibition of PDE3 by cilostamide and PDE4 by Ro 20-1724 potentiated ß₁-AR cAMP signals, whereas Glu-R cAMP was augmented only by PD4 inhibition. PGE₁-R and ß₂-AR generated substantial cAMP increases only when PDE3 and PDE4 were blocked. For all receptors except PGE₁-R, the measurements of I_Ca,L closely matched the ones obtained with CNG channels. Indeed, PDE3 and PDE4 controlled ß₁-AR and ß₂-AR regulation of I_Ca,L, whereas only PDE4 controlled Glu-R regulation of I_Ca,L thus demonstrating that receptor–PDE coupling has functional implications downstream of cAMP. PGE₁ had no effect on I_Ca,L even after blockade of PDE3 or PDE4, suggesting that other mechanisms prevent cAMP produced by PGE₁ to diffuse to L-type Ca²⁺ channels. These results identify specific functional coupling of individual PDE families to G_s-coupled receptors as a major mechanism enabling cardiac cells to generate heterogeneous cAMP signals in response to different hormones.

Key Words: cAMP • heart • G-protein–coupled receptor • phosphodiesterase

This article has been cited by other articles:

				S. Manni, J. H. Mauban, C. W. Ward, and M. Bond Phosphorylation of the cAMP-dependent Protein Kinase (PKA) Regulatory Subunit Modulates PKA-AKAP Interaction, Substrate Phosphorylation, and Calcium Signaling in Cardiac Cells J. Biol. Chem., August 29, 2008; 283(35): 24145 - 24154. [Abstract] [Full Text] [PDF]

				R. V. Iancu, G. Ramamurthy, S. Warrier, V. O. Nikolaev, M. J. Lohse, S. W. Jones, and R. D. Harvey Cytoplasmic cAMP concentrations in intact cardiac myocytes Am J Physiol Cell Physiol, August 1, 2008; 295(2): C414 - C422. [Abstract] [Full Text] [PDF]

				M. S. Hanson, A. H. Stephenson, E. A. Bowles, M. Sridharan, S. Adderley, and R. S. Sprague Phosphodiesterase 3 is present in rabbit and human erythrocytes and its inhibition potentiates iloprost-induced increases in cAMP Am J Physiol Heart Circ Physiol, August 1, 2008; 295(2): H786 - H793. [Abstract] [Full Text] [PDF]

				K.-O. Larsen, B. Lygren, I. Sjaastad, K. A. Krobert, K. Arnkvaern, G. Florholmen, A.-K. R. Larsen, F. O. Levy, K. Tasken, O. H. Skjonsberg, et al. Diastolic dysfunction in alveolar hypoxia: a role for interleukin-18-mediated increase in protein phosphatase 2A Cardiovasc Res, July 29, 2008; (2008) cvn180v2. [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]

				J. Leroy, A. Abi-Gerges, V. O. Nikolaev, W. Richter, P. Lechene, J.-L. Mazet, M. Conti, R. Fischmeister, and G. Vandecasteele Spatiotemporal Dynamics of {beta}-Adrenergic cAMP Signals and L-Type Ca2+ Channel Regulation in Adult Rat Ventricular Myocytes: Role of Phosphodiesterases Circ. Res., May 9, 2008; 102(9): 1091 - 1100. [Abstract] [Full Text] [PDF]

				D. Willoughby, G. S. Baillie, M. J. Lynch, A. Ciruela, M. D. Houslay, and D. M. F. Cooper Dynamic Regulation, Desensitization, and Cross-talk in Discrete Subcellular Microdomains during beta2-Adrenoceptor and Prostanoid Receptor cAMP Signaling J. Biol. Chem., November 23, 2007; 282(47): 34235 - 34249. [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]

				J. A. K. Birkeland, F. Swift, N. Tovsrud, U. Enger, P. K. Lunde, E. Qvigstad, F. O. Levy, O. M. Sejersted, and I. Sjaastad Serotonin increases L-type Ca2+ current and SR Ca2+ content through 5-HT4 receptors in failing rat ventricular cardiomyocytes Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2367 - H2376. [Abstract] [Full Text] [PDF]

				B.-G. Kerfant, D. Zhao, I. Lorenzen-Schmidt, L. S. Wilson, S. Cai, S. R. W. Chen, D. H. Maurice, and P. H. Backx PI3K{gamma} Is Required for PDE4, not PDE3, Activity in Subcellular Microdomains Containing the Sarcoplasmic Reticular Calcium ATPase in Cardiomyocytes Circ. Res., August 17, 2007; 101(4): 400 - 408. [Abstract] [Full Text] [PDF]

				D. Willoughby and D. M. F. Cooper Organization and Ca2+ Regulation of Adenylyl Cyclases in cAMP Microdomains Physiol Rev, July 1, 2007; 87(3): 965 - 1010. [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. Warrier, G. Ramamurthy, R. L. Eckert, V. O. Nikolaev, M. J. Lohse, and R. D. Harvey cAMP microdomains and L-type Ca2+ channel regulation in guinea-pig ventricular myocytes J. Physiol., May 1, 2007; 580(3): 765 - 776. [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]

				M. Sasseville, N. Cote, C. Vigneault, C. Guillemette, and F. J. Richard 3'5'-Cyclic Adenosine Monophosphate-Dependent Up-Regulation of Phosphodiesterase Type 3A in Porcine Cumulus Cells Endocrinology, April 1, 2007; 148(4): 1858 - 1867. [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]

				T. C. Rich, W. Xin, C. Mehats, K. A. Hassell, L. A. Piggott, X. Le, J. W. Karpen, and M. Conti Cellular mechanisms underlying prostaglandin-induced transient cAMP signals near the plasma membrane of HEK-293 cells Am J Physiol Cell Physiol, January 1, 2007; 292(1): C319 - C331. [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]

				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]

				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]