Pharmacological characterization of metabotropic glutamate receptors in several types of brain cells in primary cultures

L Prezeau, J Carrette, B Helpap, K Curry, JP Pin and J Bockaert

CNRS UPR 9023, Mecanismes Moleculaires des Communications Cellulaires, Centre CNRS-INSERM Pharmacologie-Endocrinologie, Montpellier, France.

Several cDNAs coding for metabotropic glutamate receptors (mGluR1-7) have now been isolated. mGluR1 and -5 are positively coupled to phospholipase C, whereas mGluR2, -3, -4, -6, and -7 are negatively coupled to adenylyl cyclase (AC) when they are expressed in Chinese hamster ovary or baby hamster kidney cells. However, the exact transduction mechanisms of these receptors in their natural environment remain to be determined. In a previous work, we demonstrated that striatal neurons in primary culture expressed a mGluR that is negatively coupled to AC and that has a pharmacology different from that of mGluR2. In the present study, the pharmacology of mGluRs negatively coupled to AC in several neuronal types and in glial cells was compared with the pharmacology of mGluR2, -3, and -4. Like striatal neurons, cerebral cortical neurons express a mGluR that is able to inhibit AC both in intact cells and in membrane preparations, via a pertussis toxin-sensitive G protein. This mGluR has a pharmacological profile similar to that of mGluR3, because quisqualate is active at relatively low concentrations (EC50 < 100 microM). Similar experiments revealed that cerebellar granule cells expressed mGluR2-like and mGluR4- like receptors. Striatal glial cells also expressed a mGluR negatively coupled to AC via a pertussis toxin-sensitive G protein. However, only glutamate and aspartate, and not quisqualate, 2- (carboxycyclopropyl)glycine, trans-1-aminocyclopentane-1,3- dicarboxylate, or L-2-amino-4-phosphonobutyrate, were agonists for this glial mGluR. This pharmacology is different from that of any cloned mGluR. Reverse transcription associated with polymerase chain reaction revealed that mGluR2 and mGluR3 mRNAs are present in striatal, cortical, and cerebellar neurons but not in striatal glial cells. Interestingly, mGluR4 mRNA was found at a high level in cerebellar granule cells and at a lower level in cortical neurons and glial cells. However, the mGluR4-specific agonist L-2-amino-4-phosphonobutyrate was found to inhibit AC very slightly in granule cells only. In conclusion, our data show that mGluR2- and mGluR3-like receptors can directly inhibit AC in neurons, and they raise the question of whether mGluR4 is really negatively coupled to AC in its normal environment. We also present evidence for a new mGluR subtype expressed in glial cells.

Volume 45, Issue 4, pp. 570-577, 04/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				C.-S. Zhang, F. Bertaso, V. Eulenburg, M. Lerner-Natoli, G. A. Herin, L. Bauer, J. Bockaert, L. Fagni, H. Betz, and A. Scheschonka Knock-In Mice Lacking the PDZ-Ligand Motif of mGluR7a Show Impaired PKC-Dependent Autoinhibition of Glutamate Release, Spatial Working Memory Deficits, and Increased Susceptibility to Pentylenetetrazol J. Neurosci., August 20, 2008; 28(34): 8604 - 8614. [Abstract] [Full Text] [PDF]

				J. Perroy, G. J. Gutierrez, V. Coulon, J. Bockaert, J.-P. Pin, and L. Fagni The C Terminus of the Metabotropic Glutamate Receptor Subtypes 2 and 7 Specifies the Receptor Signaling Pathways J. Biol. Chem., November 30, 2001; 276(49): 45800 - 45805. [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]

				F. Ango, J.-P. Pin, J. C. Tu, B. Xiao, P. F. Worley, J. Bockaert, and L. Fagni Dendritic and Axonal Targeting of Type 5 Metabotropic Glutamate Receptor Is Regulated by Homer1 Proteins and Neuronal Excitation J. Neurosci., December 1, 2000; 20(23): 8710 - 8716. [Abstract] [Full Text] [PDF]

				J. Perroy, L. Prezeau, M. De Waard, R. Shigemoto, J. Bockaert, and L. Fagni Selective Blockade of P/Q-Type Calcium Channels by the Metabotropic Glutamate Receptor Type 7 Involves a Phospholipase C Pathway in Neurons J. Neurosci., November 1, 2000; 20(21): 7896 - 7904. [Abstract] [Full Text] [PDF]

				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]

				N. E. Schoppa and G. L. Westbrook Modulation of mEPSCs in Olfactory Bulb Mitral Cells by Metabotropic Glutamate Receptors J Neurophysiol, September 1, 1997; 78(3): 1468 - 1475. [Abstract] [Full Text] [PDF]

				R. Pekhletski, R. Gerlai, L. S. Overstreet, X.-P. Huang, N. Agopyan, N. T. Slater, W. Abramow-Newerly, J. C. Roder, and D. R. Hampson Impaired Cerebellar Synaptic Plasticity and Motor Performance in Mice Lacking the mGluR4 Subtype of Metabotropic Glutamate Receptor J. Neurosci., October 15, 1996; 16(20): 6364 - 6373. [Abstract] [Full Text] [PDF]

				N. Stella and P. J. Magistretti Vasoactive Intestinal Peptide (VIP) and Pituitary Adenylate Cyclase-activating Polypeptide (PACAP) Potentiate the Glutamate-evoked Release of Arachidonic Acid from Mouse Cortical Neurons. EVIDENCE FOR A cAMP-INDEPENDENT MECHANISM J. Biol. Chem., September 27, 1996; 271(39): 23705 - 23710. [Abstract] [Full Text] [PDF]

				J. Perroy, S. Richard, J. Nargeot, J. Bockaert, and L. Fagni Permissive Effect of Voltage on mGlu 7 Receptor Subtype Signaling in Neurons J. Biol. Chem., January 4, 2002; 277(2): 1223 - 1228. [Abstract] [Full Text] [PDF]