Structural and conformational features determining selective signal transduction in the beta 3-adrenergic receptor

N Blin, L Camoin, B Maigret and AD Strosberg

Institut Cochin de Genetique Moleculaire, CNRS-UPR 0415, Paris, France.

With respect to the beta 1- and beta 2-adrenergic receptors (ARs), the beta 3-AR induces specific physiological effects in a few target tissues and exhibits atypical pharmacological properties that distinguish it unambiguously from its counterparts. Therefore, the beta 3-AR represents a suitable model to study the molecular mechanism responsible for receptor subtype selectivity and specificity. Potent beta 3-AR ligands newly characterized in Chinese hamster ovary cells expressing the beta 3-AR were also evaluated in Chinese hamster ovary cells expressing beta 1- and beta 2-ARs and were classified into three groups according to their pharmacological properties. Among the beta 1/beta 2/beta 3 agonists BRL 37344 and LY 79771 exhibit beta 3 selectivity in stimulating adenylyl cyclase; among the beta 1/beta 2 antagonists displaying beta 3 agonistic effects ICI 201651 exhibits beta 3-AR binding selectivity, whereas among the beta 1/beta 2/beta 3 antagonist class bupranolol is the most efficient (but not selective) beta 3-AR antagonist. The structures of these ligands were simulated and compared using computer-generated molecular modeling. Structure- activity relationship analysis indicates that potent or selective beta 3-AR compounds, in addition to possessing a pharmacophore common to all beta-AR ligands, contain a long and bulky alkylamine substituent moiety, which is able to adopt and exchange extended and stacked conformations. Computerized three-dimensional models of the beta 1-, beta 2-, and beta 3-AR binding sites show that more bulky amino acid side chains point inside the groove of the beta 1 and beta 2 sites, compared with the beta 3 site, in a region implicated in signal processing. The long alkylamine chain of compounds behaving as beta 1/beta 2 antagonists and beta 3 agonists may thus adopt either a stacked conformation in the encumbered beta 1- and beta 2-AR sites, leading to antagonistic effects, or an extended conformation in the less encumbered beta 3 site, thus interacting with specific residues implicated in signal transduction.

Volume 44, Issue 6, pp. 1094-1104, 12/01/1993
Copyright © 1993 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				M. C. Michel and A. E. Alewijnse Ligand-Directed Signaling: 50 Ways to Find a Lover Mol. Pharmacol., November 1, 2007; 72(5): 1097 - 1099. [Abstract] [Full Text] [PDF]

				J. G. Baker Evidence for a Secondary State of the Human {beta}3-Adrenoceptor Mol. Pharmacol., December 1, 2005; 68(6): 1645 - 1655. [Abstract] [Full Text] [PDF]

				V. Leblais, F. Pourageaud, M. D. Ivorra, C. Guibert, R. Marthan, and B. Muller Role of {alpha}-Adrenergic Receptors in the Effect of the {beta}-Adrenergic Receptor Ligands, CGP 12177, Bupranolol, and SR 59230A, on the Contraction of Rat Intrapulmonary Artery J. Pharmacol. Exp. Ther., April 1, 2004; 309(1): 137 - 145. [Abstract] [Full Text]

				A. A. Konkar, Z. Zhu, and J. G. Granneman Aryloxypropanolamine and Catecholamine Ligand Interactions with the beta 1-Adrenergic Receptor: Evidence for Interaction with Distinct Conformations of beta 1-Adrenergic Receptors J. Pharmacol. Exp. Ther., September 1, 2000; 294(3): 923 - 932. [Abstract] [Full Text]

				P. Pianka, Y. Oron, M. Lazar, and O. Geyer Nonadrenergic, Noncholinergic Relaxation of Bovine Iris Sphincter: Role of Endogenous Nitric Oxide Invest. Ophthalmol. Vis. Sci., March 1, 2000; 41(3): 880 - 886. [Abstract] [Full Text]

				A. A. Konkar, S. S. Vansal, G. Shams, P. F. Fraundorfer, W.-P. Zheng, V. I. Nikulin, J. D. L. Angeles, R. H. Fertel, D. D. Miller, and D. R. Feller beta -Adrenoceptor Subtype Activities of Trimetoquinol Derivatives: Biochemical Studies on Human beta -Adrenoceptors Expressed in Chinese Hamster Ovary Cells J. Pharmacol. Exp. Ther., November 1, 1999; 291(2): 875 - 883. [Abstract] [Full Text]

				E. Farias-Silva, D. M. Grassi-Kassisse, V. Wolf-Nunes, and R. C. Spadari-Bratfisch Stress-induced alteration in the lipolytic response to {beta}-adrenoceptor agonists in rat white adipocytes J. Lipid Res., September 1, 1999; 40(9): 1719 - 1727. [Abstract] [Full Text]

				M. R. Candelore, L. Deng, L. Tota, X.-M. Guan, A. Amend, Y. Liu, R. Newbold, M. A. Cascieri, and A. E. Weber Potent and Selective Human beta 3-Adrenergic Receptor Antagonists J. Pharmacol. Exp. Ther., August 1, 1999; 290(2): 649 - 655. [Abstract] [Full Text]

				C. Gauthier, G. Tavernier, J.-N. Trochu, V. Leblais, K. Laurent, D. Langin, D. Escande, and H. Le Marec Interspecies Differences in the Cardiac Negative Inotropic Effects of beta 3-Adrenoceptor Agonists J. Pharmacol. Exp. Ther., August 1, 1999; 290(2): 687 - 693. [Abstract] [Full Text]

				V. Leblais, S. Demolombe, G. Vallette, D. Langin, I. Baro, D. Escande, and C. Gauthier beta 3-Adrenoceptor Control the Cystic Fibrosis Transmembrane Conductance Regulator through a cAMP/Protein Kinase A-independent Pathway J. Biol. Chem., March 5, 1999; 274(10): 6107 - 6113. [Abstract] [Full Text] [PDF]

				R. Jockers, T. Issad, V. Zilberfarb, P. de Coppet, S. Marullo, and A. D. Strosberg Desensitization of the {beta}-Adrenergic Response in Human Brown Adipocytes Endocrinology, June 1, 1998; 139(6): 2676 - 2684. [Abstract] [Full Text] [PDF]

				J. G. Granneman, K. N. Lahners, and Y. Zhai Agonist Interactions with Chimeric and Mutant beta 1- and beta 3-Adrenergic Receptors: Involvement of the Seventh Transmembrane Region in Conferring Subtype Specificity Mol. Pharmacol., May 1, 1998; 53(5): 856 - 861. [Abstract] [Full Text]

				A. Lacroix, J. Tremblay, G. Rousseau, M. Bouvier, and P. Hamet Propranolol Therapy for Ectopic {beta}-Adrenergic Receptors in Adrenal Cushing's Syndrome N. Engl. J. Med., November 13, 1997; 337(20): 1429 - 1434. [Full Text] [PDF]

				C. Atgie, F. D'Allaire, and L. J. Bukowiecki Role of beta 1- and beta 3-adrenoceptors in the regulation of lipolysis and thermogenesis in rat brown adipocytes Am J Physiol Cell Physiol, October 1, 1997; 273(4): C1136 - C1142. [Abstract] [Full Text] [PDF]

				K. E. Hadri, A. Courtalon, X. Gauthereau, A.-M. Chambaut-Guerin, J. Pairault, and B. Feve Differential Regulation by Tumor Necrosis Factor-alpha of beta 1-, beta 2-, and beta 3-Adrenoreceptor Gene Expression in 3T3-F442A Adipocytes J. Biol. Chem., September 26, 1997; 272(39): 24514 - 24521. [Abstract] [Full Text] [PDF]

				V Zilberfarb, F Pietri-Rouxel, R Jockers, S Krief, C Delouis, T Issad, and A. Strosberg Human immortalized brown adipocytes express functional beta3-adrenoceptor coupled to lipolysis J. Cell Sci., January 4, 1997; 110(7): 801 - 807. [Abstract] [PDF]

				R. Jockers, A. D. Silva, A. D. Strosberg, M. Bouvier, and S. Marullo New Molecular and Structural Determinants Involved in beta(2)-Adrenergic Receptor Desensitization and Sequestration J. Biol. Chem., April 19, 1996; 271(16): 9355 - 9362. [Abstract] [Full Text] [PDF]

				B. Fève, F. Piétri-Rouxel, K. E. Hadri, M.-F. Drumare, and A. D. Strosberg Long Term Phorbol Ester Treatment Down-regulates the [IMAGE][IMAGE]-Adrenergic Receptor in 3T3-F442A Adipocytes J. Biol. Chem., May 5, 1995; 270(18): 10952 - 10959. [Abstract] [Full Text] [PDF]