Coupling of metabotropic glutamate receptors 2 and 4 to G alpha 15, G alpha 16, and chimeric G alpha q/i proteins: characterization of new antagonists

J Gomeza, S Mary, I Brabet, ML Parmentier, S Restituito, J Bockaert and JP Pin

UPR Centre Nationale de Recherche Scientifique 9023, Mecanismes Moleculaires des Communications Cellulaires, CCIPE, Montpeller, France.

Together with the calcium-sensing receptor, the metabotropic glutamate receptors (mGluRs) share no sequence homology with the other G protein- coupled receptors (GPCRs) and therefore constitute a new family of receptors. Recently, it was reported that G alpha 15 and G alpha 16 subunits allow many GPCRs to activate phospholipase C (PLC). Furthermore, the exchange of a few carboxyl-terminal residues of G alpha q by those of G alpha 12 or G alpha o allows the resulting chimeric G alpha subunits (G alpha ql and G alpha qol respectively) to couple Gi-coupled receptors to PLC. We report that mGluR2 and mGluR4, two receptors negatively coupled to adenylyl cyclase, activate PLC when coexpressed with G alpha 15, G alpha ql or G alpha qo. This indicates that the carboxyl-terminal end of the G alpha subunit also plays an important role in the specific interaction between mGluRs and the G proteins. In addition, the measurement of PLC activation by Gi-coupled mGluRs coexpressed with these G alpha subunits constitutes an easy functional assay for the pharmacological characterization of these receptors. The rank order of potency of antagonists was found to be (2S,3S,4S)-2-methyl-2-(carboxycyclopropyl)glycine approximately (R,S)- alpha-methyl-4-phosphonophenylglycine > (R,S)-alpha-methyl-4- sulfonophenylglycine > (R,S)-alpha-methyl-4-tetrazolylphenylglycine = (S)-2-amino-2-methyl-4-phosphonobutyrate for mGluR2 and to be (R,S)- alpha-methyl-4-phosphonophenylglycine > or = (S)-2-amino-2-methyl-4- phosphonobutyrate > > (R,S)-alpha-methyl-4-sulfonophenylglycine [(R,S)- alpha-methyl-4-tetrazolylphenylglycine and (2S,3S,4S)-2-methyl-2- (carboxycyclopropyl)glycine being inactive at 1 mM] for mGluR4. Using this functional assay, (R,S)-alpha-methyl-4-phosphonophenylglycine was found to have a similar KB value for mGluR2 and mGluR4.

Volume 50, Issue 4, pp. 923-930, 10/01/1996
Copyright © 1996 by American Society for Pharmacology and Experimental Therapeutics

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]

				M. Frauli, N. Hubert, S. Schann, N. Triballeau, H.-O. Bertrand, F. Acher, P. Neuville, J.-P. Pin, and L. Prezeau Amino-Pyrrolidine Tricarboxylic Acids Give New Insight into Group III Metabotropic Glutamate Receptor Activation Mechanism Mol. Pharmacol., March 1, 2007; 71(3): 704 - 712. [Abstract] [Full Text] [PDF]

				M. Wang, Y. Yao, D. Kuang, and D. R. Hampson Activation of Family C G-protein-coupled Receptors by the Tripeptide Glutathione J. Biol. Chem., March 31, 2006; 281(13): 8864 - 8870. [Abstract] [Full Text] [PDF]

				Patrick. M. Downey, G. Lozza, R. Petro, E. Diodato, C. Foglia, F. Bottazzoli, R. Brusa, T. Asquini, A. Reggiani, and M. Grilli Ecdysone-Based System for Controlled Inducible Expression of Metabotropic Glutamate Receptor Subtypes 2, 5, and 8 J Biomol Screen, December 1, 2005; 10(8): 841 - 848. [Abstract] [PDF]

				E. Rosemond, M. Wang, Y. Yao, L. Storjohann, T. Stormann, E. C. Johnson, and D. R. Hampson Molecular Basis for the Differential Agonist Affinities of Group III Metabotropic Glutamate Receptors Mol. Pharmacol., October 1, 2004; 66(4): 834 - 842. [Abstract] [Full Text] [PDF]

				H. Schaffhauser, B. A. Rowe, S. Morales, L. E. Chavez-Noriega, R. Yin, C. Jachec, S. P. Rao, G. Bain, A. B. Pinkerton, J.-M. Vernier, et al. Pharmacological Characterization and Identification of Amino Acids Involved in the Positive Modulation of Metabotropic Glutamate Receptor Subtype 2 Mol. Pharmacol., October 1, 2003; 64(4): 798 - 810. [Abstract] [Full Text] [PDF]

				M. Havlickova, J. Blahos, I. Brabet, J. Liu, B. Hruskova, L. Prezeau, and J.-P. Pin The Second Intracellular Loop of Metabotropic Glutamate Receptors Recognizes C Termini of G-protein {alpha}-Subunits J. Biol. Chem., September 12, 2003; 278(37): 35063 - 35070. [Abstract] [Full Text] [PDF]

				Q. Shi, J. E. Savage, S. J. Hufeisen, L. Rauser, E. Grajkowska, P. Ernsberger, J. T. Wroblewski, J. H. Nadeau, and B. L. Roth L-Homocysteine Sulfinic Acid and Other Acidic Homocysteine Derivatives Are Potent and Selective Metabotropic Glutamate Receptor Agonists J. Pharmacol. Exp. Ther., April 1, 2003; 305(1): 131 - 142. [Abstract] [Full Text]

				A. M.F. Liu, M. K.C. Ho, C. S.S. Wong, J. H.P. Chan, A. H.M. Pau, and Y. H. Wong G{alpha}[16/z] Chimeras Efficiently Link a Wide Range of G Protein-coupled Receptors to Calcium Mobilization J Biomol Screen, February 1, 2003; 8(1): 39 - 49. [Abstract] [PDF]

				A.-S. Bessis, P. Rondard, F. Gaven, I. Brabet, N. Triballeau, L. Prezeau, F. Acher, and J.-P. Pin Closure of the Venus flytrap module of mGlu8 receptor and the activation process: Insights from mutations converting antagonists into agonists PNAS, August 20, 2002; 99(17): 11097 - 11102. [Abstract] [Full Text] [PDF]

				Y.-L. Chen, C.-C. Huang, and K.-S. Hsu Time-Dependent Reversal of Long-Term Potentiation by Low-Frequency Stimulation at the Hippocampal Mossy Fiber-CA3 Synapses J. Neurosci., June 1, 2001; 21(11): 3705 - 3714. [Abstract] [Full Text] [PDF]

				F. Y. Carroll, A. Stolle, P. M. Beart, A. Voerste, I. Brabet, F. Mauler, C. Joly, H. Antonicek, J. Bockaert, T. Müller, et al. BAY36-7620: A Potent Non-Competitive mGlu1 Receptor Antagonist with Inverse Agonist Activity. Mol. Pharmacol., April 16, 2001; 59(5): 965 - 973. [Abstract] [Full Text]

				C. Romano, J. K. Miller, K. Hyrc, S. Dikranian, S. Mennerick, Y. Takeuchi, M. P. Goldberg, and K. L. O'Malley Covalent and Noncovalent Interactions Mediate Metabotropic Glutamate Receptor mGlu5 Dimerization Mol. Pharmacol., January 1, 2001; 59(1): 46 - 53. [Abstract] [Full Text]

				H. Schaffhauser, Z. Cai, F. Hubalek, T. A. Macek, J. Pohl, T. J. Murphy, and P. J. Conn cAMP-Dependent Protein Kinase Inhibits mGluR2 Coupling to G-Proteins by Direct Receptor Phosphorylation J. Neurosci., August 1, 2000; 20(15): 5663 - 5670. [Abstract] [Full Text] [PDF]

				T. Galvez, S. Urwyler, L. Prézeau, J. Mosbacher, C. Joly, B. Malitschek, J. Heid, I. Brabet, W. Froestl, B. Bettler, et al. Ca2+ Requirement for High-Affinity gamma -Aminobutyric Acid (GABA) Binding at GABAB Receptors: Involvement of Serine 269 of the GABABR1 Subunit Mol. Pharmacol., March 1, 2000; 57(3): 419 - 426. [Abstract] [Full Text]

				D. R. Hampson, X.-P. Huang, R. Pekhletski, V. Peltekova, G. Hornby, C. Thomsen, and H. Thogersen Probing the Ligand-binding Domain of the mGluR4 Subtype of Metabotropic Glutamate Receptor J. Biol. Chem., November 19, 1999; 274(47): 33488 - 33495. [Abstract] [Full Text] [PDF]

				T. Galvez, M.-L. Parmentier, C. Joly, B. Malitschek, K. Kaupmann, R. Kuhn, H. Bittiger, W. Froestl, B. Bettler, and J.-P. Pin Mutagenesis and Modeling of the GABAB Receptor Extracellular Domain Support a Venus Flytrap Mechanism for Ligand Binding J. Biol. Chem., May 7, 1999; 274(19): 13362 - 13369. [Abstract] [Full Text] [PDF]

				C. L. Linn and A. C. Gafka Activation of Metabotropic Glutamate Receptors Modulates the Voltage-Gated Sustained Calcium Current in a Teleost Horizontal Cell J Neurophysiol, February 1, 1999; 81(2): 425 - 434. [Abstract] [Full Text] [PDF]

				J. Blahos II, S. Mary, J. Perroy, C. de Colle, I. Brabet, J. Bockaert, and J.-P. Pin Extreme C Terminus of G Protein alpha -Subunits Contains a Site That Discriminates between Gi-coupled Metabotropic Glutamate Receptors J. Biol. Chem., October 2, 1998; 273(40): 25765 - 25769. [Abstract] [Full Text] [PDF]

				C. W. Fong, D. S. Bahia, S. Rees, and G. Milligan Selective Activation of a Chimeric Gi1/Gs G Protein alpha  Subunit by the Human IP Prostanoid Receptor: Analysis Using Agonist Stimulation of High Affinity GTPase Activity and [35S]Guanosine-5'-O-(3-thio)triphosphate Binding Mol. Pharmacol., August 1, 1998; 54(2): 249 - 257. [Abstract] [Full Text]

				M.-L. Parmentier, C. Joly, S. Restituito, J. Bockaert, Y. Grau, and J.-P. Pin The G Protein-Coupling Profile of Metabotropic Glutamate Receptors, as Determined with Exogenous G Proteins, Is Independent of Their Ligand Recognition Domain Mol. Pharmacol., April 1, 1998; 53(4): 778 - 786. [Abstract] [Full Text]

				N. A. Breakwell, M. J. Rowan, and R. Anwyl (+)-MCPG Blocks Induction of LTP in CA1 of Rat Hippocampus via Agonist Action at an mGluR Group II Receptor J Neurophysiol, March 1, 1998; 79(3): 1270 - 1276. [Abstract] [Full Text] [PDF]

				S. Mary, J. Gomeza, L. Prezeau, J. Bockaert, and J.-P. Pin A Cluster of Basic Residues in the Carboxyl-terminal Tail of the Short Metabotropic Glutamate Receptor 1 Variants Impairs Their Coupling to Phospholipase C J. Biol. Chem., January 2, 1998; 273(1): 425 - 432. [Abstract] [Full Text] [PDF]

				J. A. Saugstad, J. M. Kinzie, M. M. Shinohara, T. P. Segerson, and G. L. Westbrook Cloning and Expression of Rat Metabotropic Glutamate Receptor 8 Reveals a Distinct Pharmacological Profile Mol. Pharmacol., January 1, 1997; 51(1): 119 - 125. [Abstract] [Full Text]

				J. Blahos, T. Fischer, I. Brabet, D. Stauffer, G. Rovelli, J. Bockaert, and J.-P. Pin A Novel Site on the Galpha -protein That Recognizes Heptahelical Receptors J. Biol. Chem., January 26, 2001; 276(5): 3262 - 3269. [Abstract] [Full Text] [PDF]

				T. Galvez, L. Prezeau, G. Milioti, M. Franek, C. Joly, W. Froestl, B. Bettler, H.-O. Bertrand, J. Blahos, and J.-P. Pin Mapping the Agonist-binding Site of GABAB Type 1 Subunit Sheds Light on the Activation Process of GABAB Receptors J. Biol. Chem., December 22, 2000; 275(52): 41166 - 41174. [Abstract] [Full Text] [PDF]