HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 28, 29085-29091, July 9, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/28/29085    most recent M400930200v1 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Binet, V. Articles by Prézeau, L. Search for Related Content PubMed PubMed Citation Articles by Binet, V. Articles by Prézeau, L. Social Bookmarking                      What's this?

The Heptahelical Domain of GABA_B2 Is Activated Directly by CGP7930, a Positive Allosteric Modulator of the GABA_B Receptor^*

Virginie Binet, Carole Brajon, Laurent Le Corre, Francine Acher, Jean-Philippe Pin, and Laurent Prézeau¶

From the Department of Molecular Pharmacology, Laboratory of Functional Genomic, CNRS UPR2580, Centre CNRS-INSERM de Pharmacologie et Endocrinologie, Montpellier 34094 cedex 5, France and Laboratory of Pharmacological and Toxicological Chemistry and Biochemistry, UMR8601-CNRS, University René Descartes-Paris V, Paris 75270 cedex 6, France

The -aminobutyric acid, type B (GABA_B) receptor is well recognized as being composed of two subunits, GABA_B1 and GABA_B2. Both subunits share structural homology with other class-III G-protein-coupled receptors. They are composed of two main domains: a heptahelical domain (HD) typical of all G-protein-coupled receptors and a large extracellular domain (ECD). Although GABA_B1 binds GABA, GABA_B2 is required for GABA_B1 to reach the cell surface. However, it is still not demonstrated whether the association of these two subunits is always required for function in the brain. Indeed, GABA_B2 plays a major role in the coupling of the heteromer to G-proteins, such that it is possible that GABA_B2 can transmit a signal in the absence of GABA_B1. Today only ligands interacting with GABA_B1 ECD have been identified. Thus, the compounds acting exclusively on the GABA_B2 subunit will be helpful in analyzing the specific role of this subunit in the brain. Here, we explored the mechanism of action of CGP7930, a compound described as a positive allosteric regulator of the GABA_B receptor. We showed that it activates the wild type GABA_B receptor but with a low efficacy. The GABA_B2 HD is necessary for this effect, although one cannot exclude that CGP7930 could also bind to GABA_B1. Of interest, CGP7930 could activate GABA_B2 expressed alone and is the first described agonistof GABA_B2. Finally, we show that CGP7930 retains its agonist activity on a GABA_B2 subunit deleted of its ECD. This demonstrates that the HD of GABA_B2 behaves similar to a rhodopsin-like receptor, because it can reach the cell surface alone, can couple to G-protein, and be activated by agonists. These data open new strategies for studying the mechanism of activation of GABA_B receptor and examine any possible role of homomeric GABA_B2 receptors.

Received for publication, January 28, 2004 , and in revised form, May 4, 2004.

^* This work was supported in part by grants from the CNRS, the Action Incitative "Molécules et Cibles Thérapeutiques" from INSERM, CNRS and the French government (to J.-P. P.), and by Addex Pharmaceuticals (Geneva, Switzerland). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Molecular Pharmacology, Laboratory for Functional Genomic, CNRS UPR-2580, 141 rue de la Cardonille, F-34094 Montpellier Cedex 5, France. Tel.: 33-467-14-2933; Fax: 33-467-54-2432; E-mail: lprezeau{at}ccipe.cnrs.fr.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				V. Binet, B. Duthey, J. Lecaillon, C. Vol, J. Quoyer, G. Labesse, J.-P. Pin, and L. Prezeau Common Structural Requirements for Heptahelical Domain Function in Class A and Class C G Protein-coupled Receptors J. Biol. Chem., April 20, 2007; 282(16): 12154 - 12163. [Abstract] [Full Text] [PDF]

				L. B. Knudsen, D. Kiel, M. Teng, C. Behrens, D. Bhumralkar, J. T. Kodra, J. J. Holst, C. B. Jeppesen, M. D. Johnson, J. C. de Jong, et al. From the Cover: Small-molecule agonists for the glucagon-like peptide 1 receptor PNAS, January 16, 2007; 104(3): 937 - 942. [Abstract] [Full Text] [PDF]

				D. S. Dupuis, D. Relkovic, L. Lhuillier, J. Mosbacher, and K. Kaupmann Point Mutations in the Transmembrane Region of GABAB2 Facilitate Activation by the Positive Modulator N,N'-Dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) in the Absence of the GABAB1 Subunit Mol. Pharmacol., December 1, 2006; 70(6): 2027 - 2036. [Abstract] [Full Text] [PDF]

				R. S. Mukherjee, E. W. McBride, M. Beinborn, K. Dunlap, and A. S. Kopin Point Mutations in Either Subunit of the GABAB Receptor Confer Constitutive Activity to the Heterodimer Mol. Pharmacol., October 1, 2006; 70(4): 1406 - 1413. [Abstract] [Full Text] [PDF]

				P. Rondard, J. Liu, S. Huang, F. Malhaire, C. Vol, A. Pinault, G. Labesse, and J.-P. Pin Coupling of Agonist Binding to Effector Domain Activation in Metabotropic Glutamate-like Receptors J. Biol. Chem., August 25, 2006; 281(34): 24653 - 24661. [Abstract] [Full Text] [PDF]

				Y. Chen, N. Menendez-Roche, and E. Sher Differential Modulation by the GABAB Receptor Allosteric Potentiator 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethylpropyl)-phenol (CGP7930) of Synaptic Transmission in the Rat Hippocampal CA1 Area J. Pharmacol. Exp. Ther., June 1, 2006; 317(3): 1170 - 1177. [Abstract] [Full Text] [PDF]

				K. Mitsukawa, R. Yamamoto, S. Ofner, J. Nozulak, O. Pescott, S. Lukic, N. Stoehr, C. Mombereau, R. Kuhn, K. H. McAllister, et al. From The Cover: A selective metabotropic glutamate receptor 7 agonist: Activation of receptor signaling via an allosteric site modulates stress parameters in vivo PNAS, December 20, 2005; 102(51): 18712 - 18717. [Abstract] [Full Text] [PDF]

				K. Ray, J. Tisdale, R. H. Dodd, P. Dauban, M. Ruat, and J. K. Northup Calindol, a Positive Allosteric Modulator of the Human Ca2+ Receptor, Activates an Extracellular Ligand-binding Domain-deleted Rhodopsin-like Seven-transmembrane Structure in the Absence of Ca2+ J. Biol. Chem., November 4, 2005; 280(44): 37013 - 37020. [Abstract] [Full Text] [PDF]

				P. Jiang, M. Cui, B. Zhao, L. A. Snyder, L. M. J. Benard, R. Osman, M. Max, and R. F. Margolskee Identification of the Cyclamate Interaction Site within the Transmembrane Domain of the Human Sweet Taste Receptor Subunit T1R3 J. Biol. Chem., October 7, 2005; 280(40): 34296 - 34305. [Abstract] [Full Text] [PDF]

				B. Holst, E. Brandt, A. Bach, A. Heding, and T. W. Schwartz Nonpeptide and Peptide Growth Hormone Secretagogues Act Both as Ghrelin Receptor Agonist and as Positive or Negative Allosteric Modulators of Ghrelin Signaling Mol. Endocrinol., September 1, 2005; 19(9): 2400 - 2411. [Abstract] [Full Text] [PDF]

				C. Goudet, J. Kniazeff, V. Hlavackova, F. Malhaire, D. Maurel, F. Acher, J. Blahos, L. Prezeau, and J.-P. Pin Asymmetric Functioning of Dimeric Metabotropic Glutamate Receptors Disclosed by Positive Allosteric Modulators J. Biol. Chem., July 1, 2005; 280(26): 24380 - 24385. [Abstract] [Full Text] [PDF]

				P. Jiang, M. Cui, B. Zhao, Z. Liu, L. A. Snyder, L. M. J. Benard, R. Osman, R. F. Margolskee, and M. Max Lactisole Interacts with the Transmembrane Domains of Human T1R3 to Inhibit Sweet Taste J. Biol. Chem., April 15, 2005; 280(15): 15238 - 15246. [Abstract] [Full Text] [PDF]