title: Endogenous sulphur-containing amino acids: potent agonists at presynaptic metabotropic glutamate autoreceptors in the rat central nervous system.
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.
authors.affiliation: Department of Neuroinflammation, Imperial College School of Medicine, Charing Cross Hospital, Fulham Palace Road, London W6 8RF. m.croucher@ic.ac.uk
authors.forename: M J
authors.initials: MJ
authors.lastname: Croucher
authors.forename: L S
authors.initials: LS
authors.lastname: Thomas
authors.forename: H
authors.initials: H
authors.lastname: Ahmadi
authors.forename: V
authors.initials: V
authors.lastname: Lawrence
authors.forename: J R
authors.initials: JR
authors.lastname: Harris
mesh_terms: D000603:Amino Acids, Sulfur / Q000494:pharmacology* / Q000502:physiology; D000818:Animals; D001224:Aspartic Acid / Q000187:drug effects / Q000378:metabolism; D017660:Autoreceptors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D003544:Cysteic Acid / Q000494:pharmacology; D003545:Cysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D018377:Neurotransmitter Agents; D017729:Presynaptic Terminals / Q000378:metabolism; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D012118:Resorcinols / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D014316:Tritium; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D000603:Amino Acids, Sulfur; D017660:Autoreceptors; D018691:Excitatory Amino Acid Antagonists; D018377:Neurotransmitter Agents; D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; D012118:Resorcinols; D014316:Tritium; D001224:Aspartic Acid; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; C079215:3,5-dihydroxyphenylglycine; C121465:6-methyl-2-(phenylethynyl)pyridine; D003544:Cysteic Acid; D003545:Cysteine; D002118:Calcium; D005998:Glycine; C013461:cysteine sulfinic acid