Endogenous sulphur-containing amino acids: potent agonists at presynaptic metabotropic glutamate autoreceptors in the rat central nervous system
Article first published online: 29 JAN 2009
2001 British Pharmacological Society
British Journal of Pharmacology
Volume 133, Issue 6, pages 815–824, July 2001
How to Cite
Croucher, M. J., Thomas, L. S., Ahmadi, H., Lawrence, V. and Harris, J. R. (2001), Endogenous sulphur-containing amino acids: potent agonists at presynaptic metabotropic glutamate autoreceptors in the rat central nervous system. British Journal of Pharmacology, 133: 815–824. doi: 10.1038/sj.bjp.0704138
- Issue published online: 29 JAN 2009
- Article first published online: 29 JAN 2009
- (Received November 23, 2000, Revised April 30, 2001, Accepted April 30, 2001)
- Sulphur-containing amino acids;
- L-cysteic acid;
- L-cysteine sulphinic acid;
- mGlu receptors;
- glutamate release;
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 [3H]-D-aspartate from rat forebrain hemisections.
Both CA (3 – 100 μM) and CSA (1 – 100 μM), in addition to the selective group I mGlu receptor agonist, (S)-3,5-dihydroxyphenylglycine ((S)-DHPG), concentration-dependently enhanced electrically-stimulated efflux of [3H]-D-aspartate from the rat forebrain slices. Basal efflux of label remained unchanged.
The inhibitory activity of the broad spectrum mGlu receptor antagonist, (±)-α-methyl-4-carboxyphenylglycine ((±)-MCPG; 200 μM), coupled with the inactivity of the selective mGlu1 receptor antagonists, (R,S)-1-aminoindan-1,5-dicarboxylic acid ((R,S)-AIDA; 100 – 500 μM) and the more potent (+)-2-methyl-4-carboxyphenylglycine (LY367385; 10 μM) 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 μM). The observed enhancement of the responses to high concentrations of CA by the selective mGlu5 receptor desensitization inhibitor, cyclothiazide (CYZ; 10 μM), 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.
British Journal of Pharmacology (2001) 133, 815–824; doi:10.1038/sj.bjp.0704138