Endogenous sulphur‐containing amino acids: potent agonists at presynaptic metabotropic glutamate autoreceptors in the rat central nervous system
- 1 July 2001
- journal article
- Published by Wiley in British Journal of Pharmacology
- Vol. 133 (6), 815-824
- https://doi.org/10.1038/sj.bjp.0704138
Abstract
We have recently demonstrated that presynaptically located metabotropic glutamate (mGlu) autoreceptors regulate synaptic glutamate release both in vitro and in vivo. We now report a positive modulatory action of the sulphur-containing amino acids (SCAAs), L-cysteic acid (CA) and L-cysteine sulphinic acid (CSA), at presynaptic group I mGlu receptors, specifically of the mGlu5 subtype, acting to enhance synaptic glutamate release from the rat forebrain in vitro. Neuronal glutamate release was monitored using electrically-evoked efflux of preloaded [(3)H]-D-aspartate from rat forebrain hemisections. Both CA (3 - 100 muM) and CSA (1 - 100 microM), in addition to the selective group I mGlu receptor agonist, (S)-3,5-dihydroxyphenylglycine ((S)-DHPG), concentration-dependently enhanced electrically-stimulated efflux of [(3)H]-D-aspartate from the rat forebrain slices. Basal efflux of label remained unchanged. The inhibitory activity of the broad spectrum mGlu receptor antagonist, (+/-)-alpha-methyl-4-carboxyphenylglycine ((+/-)-MCPG; 200 microM), coupled with the inactivity of the selective mGlu1 receptor antagonists, (R,S)-1-aminoindan-1,5-dicarboxylic acid ((R,S)-AIDA; 100 - 500 microM) and the more potent (+)-2-methyl-4-carboxyphenylglycine (LY367385; 10 microM) against these responses, indicates an action of the SCAAs at the mGlu5 receptor subtype. This proposal is supported by the potent inhibition of these responses by the selective, non-competitive mGlu5 receptor antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP; 10 microM). The observed enhancement of the responses to high concentrations of CA by the selective mGlu5 receptor desensitization inhibitor, cyclothiazide (CYZ; 10 microM), is also consistent with this concept. Administration of the agonists in the presence of bovine serum albumin (BSA; 5 - 15 mg ml(-1)) markedly attenuated the positive modulatory responses observed, strongly supporting a role for arachidonic acid in the expression of these mGlu5 receptor-mediated responses. The regulatory actions of SCAAs on synaptic glutamate release demonstrated in the present study may provide a physiological function for these putative neurotransmitter amino acids in the mammalian brain. These central actions of the SCAAs may have wide-ranging implications for a range of neurological and neuropsychiatric disease states and their treatment.Keywords
This publication has 60 references indexed in Scilit:
- The neurotransmitter candidature of sulphur-containing excitatory amino acids in the mammalian central nervous systemPharmacology & Therapeutics, 1996
- Comparison of the superfused efflux of preaccumulated d-[3H]aspartate and endogenous l-aspartate and l-glutamate from rat cerebrocortical minislicesNeurochemistry International, 1994
- Cyclothiazide differentially modulates human metabotropic glutamate receptors linked to phosphoinositide hydrolysis stimulation in oocytesEuropean Journal of Pharmacology: Molecular Pharmacology, 1994
- Glutamate Exocytosis and MARCKS Phosphorylation Are Enhanced by a Metabotropic Glutamate Receptor Coupled to a Protein Kinase C Synergistically Activated by Diacylglycerol and Arachidonic AcidJournal of Neurochemistry, 1994
- The depolarization-induced outflow of d-[3H]aspartate from rat brain slices is modulated by metabotropic glutamate receptorsNeurochemistry International, 1994
- Kindling of full limbic seizures by repeated microinjections of excitatory amino acids into the rat amygdalaBrain Research, 1989
- dl-2-[3,4-3H]Amino-4-phosphonobutyrate binding sites in the rat hippocampus: distribution and possible physiological roleBrain Research, 1987
- Potassium and veratrine-stimulated l-[3H]cysteine sulfinate and l-[3H]glutamate release from rat brain slices☆Neurochemistry International, 1984
- Evidence for cysteine sulfinate as a neurotransmitterBrain Research, 1982
- Cysteine Sulfinic Acid in the Central Nervous System: Specific Binding of [35S]Cysteic Acid to Cortical Synaptic Membranes‐An Investigation of Possible Binding Sites for Cysteine Sulfinic AcidJournal of Neurochemistry, 1982