Metabotropic glutamate receptors negatively coupled to adenylate cyclase inhibit N-methyl-D-aspartate receptor activity and prevent neurotoxicity in mesencephalic neurons in vitro

A Ambrosini, L Bresciani, S Fracchia, N Brunello and G Racagni

Center of Neuropharmacology, University of Milan, Italy.

The functional effects of G protein-linked glutamate receptor activation have been studied in mouse mesencephalic neurons in vitro. We have been able to identify two receptor classes, one linked to phosphoinositide hydrolysis and another that inhibits adenylate cyclase. The agonist (1S,3R)-aminocyclopentane-1,3-dicarboxylate (ACPD) affected the two responses with similar potency (EC50 = 2 and 7 microM, respectively). In contrast, (2S,3S,4S)-alpha- (carboxycyclopropyl)glycine selectively decreased adenylate cyclase activity (EC50 = 150 nM), without interfering with the phosphoinositide pathway. Activation of ion channel-linked glutamate receptors in mesencephalic neurons leads to cGMP formation. In this study, we demonstrate that cell pretreatment with ACPD or (2S,3S,4S)-alpha- (carboxycyclopropyl)glycine prevented, in a dose-dependent fashion, N- methyl-D-aspartate (NMDA)-induced cGMP formation but not the kainate- stimulated response. The pharmacological profile suggests that receptors that are negatively coupled to adenylate cyclase are responsible for this effect. Coexposure of neurons to ACPD and Ba2+, a K+ channel blocker, counteracted the ACPD-induced blockade of NMDA receptors, suggesting that activation of K+ conductances could be involved in the post-transduction events triggered by metabotropic receptors in the mesencephalon. Neuronal treatment with NMDA for 10 min caused a reduction in mitochondrial activity. Direct inhibition of nitric oxide synthase with the inhibitor NG-nitro-L-arginine or removal of extracellular nitric oxide with reduced hemoglobin did not prevent this metabolic impairment, thus excluding a role for nitric oxide in this test for excitotoxicity. On the contrary, the mitochondrial function was maintained when neurons exposed to NMDA were preincubated with metabotropic receptor agonists. To summarize, our results suggest that metabotropic receptors that are negatively coupled to adenylate cyclase exert modulatory control specifically on NMDA receptor activity. This event could also contribute to the reduction of neurotoxic effects due to NMDA receptor hyperactivity.

Volume 47, Issue 5, pp. 1057-1064, 05/01/1995
Copyright © 1995 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				C. Corti, G. Battaglia, G. Molinaro, B. Riozzi, A. Pittaluga, M. Corsi, M. Mugnaini, F. Nicoletti, and V. Bruno The Use of Knock-Out Mice Unravels Distinct Roles for mGlu2 and mGlu3 Metabotropic Glutamate Receptors in Mechanisms of Neurodegeneration/Neuroprotection J. Neurosci., August 1, 2007; 27(31): 8297 - 8308. [Abstract] [Full Text] [PDF]

				A. Contractor, R. W. Gereau IV, T. Green, and S. F. Heinemann Direct effects of metabotropic glutamate receptor compounds on native and recombinant N-methyl-D-aspartate receptors PNAS, July 21, 1998; 95(15): 8969 - 8974. [Abstract] [Full Text] [PDF]

				G. Martin, Z. Nie, and G. R. Siggins Metabotropic Glutamate Receptors Regulate N-Methyl-D-Aspartate-Mediated Synaptic Transmission in Nucleus Accumbens J Neurophysiol, December 1, 1997; 78(6): 3028 - 3038. [Abstract] [Full Text] [PDF]

				V. Neugebauer, N. B. Keele, and P. Shinnick-Gallagher Epileptogenesis In Vivo Enhances the Sensitivity of Inhibitory Presynaptic Metabotropic Glutamate Receptors in Basolateral Amygdala Neurons In Vitro J. Neurosci., February 1, 1997; 17(3): 983 - 995. [Abstract] [Full Text] [PDF]