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Vol. 53, Issue 4, 527-552, December 2001
Department of Physiology and Pharmacology, Section of
Molecular Neuropharmacology, Karolinska Institutet, Stockholm, Sweden
(B.B.F.); Leiden/Amsterdam Center for Drug Research, Gorlaeus
Laboratories, Leiden, The Netherlands (A.P.I.); Molecular Recognition
Section, National Institutes of Health, Bethesda, Maryland (K.A.J.);
Institut für Pharmakologie und Toxikologie,
Universität Würzburg,
Würzburg, Germany (K.-N.K.); and Department of
Physiology, Health Sciences Center, University of Virginia,
Charlottesville, Virginia (J.L.)
I. Introduction
II. Molecular Basis for Receptor Nomenclature
III. Formation and Levels of the Endogenous Agonist Adenosine
IV. Structure
V. Gene Structure
VI. Binding Sites As Revealed by Site-Directed Mutagenesis
VII. Distribution
VIII. Classification of Adenosine Receptors Using Pharmacological
Tools
IX. Signaling
A. G Protein Coupling
B. Second Messengers and Signals
C. Adenosine Receptor-Mediated Changes in Cell Proliferation and in
Mitogen-Activated Protein Kinase Activation
D. Interactions with Other Receptor Systems
X. Receptor Regulation
XI. Assay Systems
XII. Physiological Roles
Therapeutic Potential
References
Four adenosine receptors have been cloned and characterized from several mammalian species. The receptors are named adenosine A1, A2A, A2B, and A3. The A2A and A2B receptors preferably interact with members of the Gs family of G proteins and the A1 and A3 receptors with Gi/o proteins. However, other G protein interactions have also been described. Adenosine is the preferred endogenous agonist at all these receptors, but inosine can also activate the A3 receptor. The levels of adenosine seen under basal conditions are sufficient to cause some activation of all the receptors, at least where they are abundantly expressed. Adenosine levels during, e.g., ischemia can activate all receptors even when expressed in low abundance. Accordingly, experiments with receptor antagonists and mice with targeted disruption of adenosine A1, A2A, and A3 expression reveal roles for these receptors under physiological and particularly pathophysiological conditions. There are pharmacological tools that can be used to classify A1, A2A, and A3 receptors but few drugs that interact selectively with A2B receptors. Testable models of the interaction of these drugs with their receptors have been generated by site-directed mutagenesis and homology-based modelling. Both agonists and antagonists are being developed as potential drugs.
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A. Mohsenin, M. D. Burdick, J. G. Molina, M. P. Keane, and M. R. Blackburn Enhanced CXCL1 production and angiogenesis in adenosine-mediated lung disease FASEB J, April 1, 2007; 21(4): 1026 - 1036. [Abstract] [Full Text] [PDF]
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 L. Carrega, E. Fenouillet, P. Giaime, A. Charavil, L. Mercier, V. Gerolami, J.-L. Berge-Lefranc, Y. Berland, J. Ruf, A. Saadjian, et al. Influence of haemodialysis and left ventricular failure on peripheral A2A adenosine receptor expression Nephrol. Dial. Transplant., March 1, 2007; 22(3): 851 - 856. [Abstract] [Full Text] [PDF]
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Q. Li, K. Ye, C. C. Blad, H. den Dulk, J. Brouwer, A. P. IJzerman, and M. W. Beukers ZM241385, DPCPX, MRS1706 Are Inverse Agonists with Different Relative Intrinsic Efficacies on Constitutively Active Mutants of the Human Adenosine A2B Receptor J. Pharmacol. Exp. Ther., February 1, 2007; 320(2): 637 - 645. [Abstract] [Full Text] [PDF]
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S. Ryzhov, J. L. McCaleb, A. E. Goldstein, I. Biaggioni, and I. Feoktistov Role of Adenosine Receptors in the Regulation of Angiogenic Factors and Neovascularization in Hypoxia J. Pharmacol. Exp. Ther., February 1, 2007; 320(2): 565 - 572. [Abstract] [Full Text] [PDF]
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S. Husain, T. W. Shearer, and C. E. Crosson Mechanisms Linking Adenosine A1 Receptors and Extracellular Signal-Regulated Kinase 1/2 Activation in Human Trabecular Meshwork Cells J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 258 - 265. [Abstract] [Full Text] [PDF]
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R. D. Lasley, G. Kristo, B. J. Keith, and R. M. Mentzer Jr. The A2a/A2b receptor antagonist ZM-241385 blocks the cardioprotective effect of adenosine agonist pretreatment in in vivo rat myocardium Am J Physiol Heart Circ Physiol, January 1, 2007; 292(1): H426 - H431. [Abstract] [Full Text] [PDF]
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Y. Chen, R. Corriden, Y. Inoue, L. Yip, N. Hashiguchi, A. Zinkernagel, V. Nizet, P. A. Insel, and W. G. Junger ATP Release Guides Neutrophil Chemotaxis via P2Y2 and A3 Receptors Science, December 15, 2006; 314(5806): 1792 - 1795. [Abstract] [Full Text] [PDF]
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B. M. Lewis, A. Pexa, K. Francis, V. Verma, A. M. McNicol, M. Scanlon, A. Deussen, W. H. Evans, D. A. Rees, and J. Ham Adenosine stimulates connexin 43 expression and gap junctional communication in pituitary folliculostellate cells FASEB J, December 1, 2006; 20(14): 2585 - 2587. [Abstract] [Full Text] [PDF]
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J. Wang and V. H. Huxley Adenosine A2A receptor modulation of juvenile female rat skeletal muscle microvessel permeability Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H3094 - H3105. [Abstract] [Full Text] [PDF]
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 A. Ilie, D. Ciocan, A.-M. Zagrean, D. A. Nita, L. Zagrean, and M. Moldovan Endogenous Activation of Adenosine A1 Receptors Accelerates Ischemic Suppression of Spontaneous Electrocortical Activity J Neurophysiol, November 1, 2006; 96(5): 2809 - 2814. [Abstract] [Full Text] [PDF]
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H. W. J. Young, C.-X. Sun, C. M. Evans, B. F. Dickey, and M. R. Blackburn A3 Adenosine Receptor Signaling Contributes to Airway Mucin Secretion after Allergen Challenge Am. J. Respir. Cell Mol. Biol., November 1, 2006; 35(5): 549 - 558. [Abstract] [Full Text] [PDF]
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H. Zhong, Y. Wu, L. Belardinelli, and D. Zeng A2B Adenosine Receptors Induce IL-19 from Bronchial Epithelial Cells, Resulting in TNF-{alpha} Increase Am. J. Respir. Cell Mol. Biol., November 1, 2006; 35(5): 587 - 592. [Abstract] [Full Text] [PDF]
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M. Faria, T. Magalhaes-Cardoso, J.-M. Lafuente-de-Carvalho, and P. Correia-de-Sa Corpus Cavernosum from Men with Vasculogenic Impotence Is Partially Resistant to Adenosine Relaxation due to Endothelial A2B Receptor Dysfunction J. Pharmacol. Exp. Ther., October 1, 2006; 319(1): 405 - 413. [Abstract] [Full Text] [PDF]
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M. F. Ethier and J. M. Madison Adenosine A1 Receptors Mediate Mobilization of Calcium in Human Bronchial Smooth Muscle Cells Am. J. Respir. Cell Mol. Biol., October 1, 2006; 35(4): 496 - 502. [Abstract] [Full Text] [PDF]
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R. P. Vaughan, M. T. Szewczyk Jr, M. J. Lanosa, C. R. DeSesa, G. Gianutsos, and J. B. Morris Adenosine Sensory Transduction Pathways Contribute to Activation of the Sensory Irritation Response to Inspired Irritant Vapors Toxicol. Sci., October 1, 2006; 93(2): 411 - 421. [Abstract] [Full Text] [PDF]
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 J. Mojsilovic-Petrovic, G.-B. Jeong, A. Crocker, A. Arneja, S. David, D. Russell, and R. G. Kalb Protecting Motor Neurons from Toxic Insult by Antagonism of Adenosine A2a and Trk Receptors J. Neurosci., September 6, 2006; 26(36): 9250 - 9263. [Abstract] [Full Text] [PDF]
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E. Y. Tan, C. L. Richard, H. Zhang, D. W. Hoskin, and J. Blay Adenosine downregulates DPPIV on HT-29 colon cancer cells by stimulating protein tyrosine phosphatase(s) and reducing ERK1/2 activity via a novel pathway Am J Physiol Cell Physiol, September 1, 2006; 291(3): C433 - C444. [Abstract] [Full Text] [PDF]
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B. Chuaychoo, M.-G. Lee, M. Kollarik, R. Pullmann Jr, and B. J. Undem Evidence for both adenosine A1 and A2A receptors activating single vagal sensory C-fibres in guinea pig lungs J. Physiol., September 1, 2006; 575(2): 481 - 490. [Abstract] [Full Text] [PDF]
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A. Ohta, E. Gorelik, S. J. Prasad, F. Ronchese, D. Lukashev, M. K. K. Wong, X. Huang, S. Caldwell, K. Liu, P. Smith, et al. A2A adenosine receptor protects tumors from antitumor T cells PNAS, August 29, 2006; 103(35): 13132 - 13137. [Abstract] [Full Text] [PDF]
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S. Ryzhov, A. E. Goldstein, I. Biaggioni, and I. Feoktistov Cross-Talk between Gs- and Gq-Coupled Pathways in Regulation of Interleukin-4 by A2B Adenosine Receptors in Human Mast Cells Mol. Pharmacol., August 1, 2006; 70(2): 727 - 735. [Abstract] [Full Text] [PDF]
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W. Yu, L. C. Zacharia, E. K. Jackson, and G. Apodaca Adenosine receptor expression and function in bladder uroepithelium Am J Physiol Cell Physiol, August 1, 2006; 291(2): C254 - C265. [Abstract] [Full Text] [PDF]
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K.-i. Otsuguro, Y. Yamaji, M. Ban, T. Ohta, and S. Ito Involvement of adenosine in depression of synaptic transmission during hypercapnia in isolated spinal cord of neonatal rats J. Physiol., August 1, 2006; 574(3): 835 - 847. [Abstract] [Full Text] [PDF]
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V. Vallon, B. Muhlbauer, and H. Osswald Adenosine and kidney function. Physiol Rev, July 1, 2006; 86(3): 901 - 940. [Abstract] [Full Text] [PDF]
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 A. Zernecke, K. Bidzhekov, B. Ozuyaman, L. Fraemohs, E. A. Liehn, J. M. Luscher-Firzlaff, B. Luscher, J. Schrader, and C. Weber CD73/Ecto-5'-Nucleotidase Protects Against Vascular Inflammation and Neointima Formation Circulation, May 2, 2006; 113(17): 2120 - 2127. [Abstract] [Full Text] [PDF]
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 I. C. Cavalcante, M. V. Castro, A. R. F. Barreto, G. W. Sullivan, M. Vale, P. R. C. Almeida, J. Linden, J. M. Rieger, F. Q. Cunha, R. L. Guerrant, et al. Effect of Novel A2A Adenosine Receptor Agonist ATL 313 on Clostridium difficile Toxin A-Induced Murine Ileal Enteritis. Infect. Immun., May 1, 2006; 74(5): 2606 - 2612. [Abstract] [Full Text] [PDF]
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Z. H. Nemeth, B. Csoka, J. Wilmanski, D. Xu, Q. Lu, C. Ledent, E. A. Deitch, P. Pacher, Z. Spolarics, and G. Hasko Adenosine A2A Receptor Inactivation Increases Survival in Polymicrobial Sepsis J. Immunol., May 1, 2006; 176(9): 5616 - 5626. [Abstract] [Full Text] [PDF]
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O. Bonneau, D. Wyss, S. Ferretti, C. Blaydon, C. S. Stevenson, and A. Trifilieff Effect of adenosine A2A receptor activation in murine models of respiratory disorders Am J Physiol Lung Cell Mol Physiol, May 1, 2006; 290(5): L1036 - L1043. [Abstract] [Full Text] [PDF]
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R. D. Brown, P. Thoren, A. Steege, R. Mrowka, J. Sallstrom, O. Skott, B. B. Fredholm, and A. E. G. Persson Influence of the adenosine A1 receptor on blood pressure regulation and renin release Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2006; 290(5): R1324 - R1329. [Abstract] [Full Text] [PDF]
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Y. Wei, P. Sun, Z. Wang, B. Yang, M. A. Carroll, and W.-H. Wang Adenosine inhibits ENaC via cytochrome P-450 epoxygenase-dependent metabolites of arachidonic acid Am J Physiol Renal Physiol, May 1, 2006; 290(5): F1163 - F1168. [Abstract] [Full Text] [PDF]
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J. B. Volmer, L. F. Thompson, and M. R. Blackburn Ecto-5'-Nucleotidase (CD73)-Mediated Adenosine Production Is Tissue Protective in a Model of Bleomycin-Induced Lung Injury J. Immunol., April 1, 2006; 176(7): 4449 - 4458. [Abstract] [Full Text] [PDF]
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N. D. Khoa, M. Postow, J. Danielsson, and B. N. Cronstein Tumor Necrosis Factor-{alpha} Prevents Desensitization of G{alpha}s-Coupled Receptors by Regulating GRK2 Association with the Plasma Membrane Mol. Pharmacol., April 1, 2006; 69(4): 1311 - 1319. [Abstract] [Full Text] [PDF]
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 N P Riksen, P Barrera, P H H van den Broek, P L C M van Riel, P Smits, and G A Rongen Methotrexate modulates the kinetics of adenosine in humans in vivo Ann Rheum Dis, April 1, 2006; 65(4): 465 - 470. [Abstract] [Full Text] [PDF]
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