2542485

Structure-function studies on N-oxalyl-diamino-dicarboxylic acids and excitatory amino acid receptors: evidence that beta-L-ODAP is a selective non-NMDA agonist.

Article date: 1989/6/1

PubMed ID: 2542485

Journal name: The Journal of neuroscience : the official journal of the Society for Neuroscience (ISSN: 0270-6474)

ABSTRACT

Excitatory amino acids and their receptors play an important role in both normal synaptic transmission and excitotoxic-mediated neuronal death. In the present investigation we have prepared a series of glutamate analogs and examined the pharmacological specificity with which they interact with excitatory amino acid receptors. Included within this group of compounds is a potent excitotoxic amino acid, beta-N-oxalyl-L-alpha, beta-diaminopropionic acid (beta-L-ODAP). This excitotoxin is of particular interest because it has been identified as a major causative agent of human neurolathyrism, a disease characterized by permanent spastic paralysis. The site of action of beta-L-ODAP was delineated with both electrophysiological recordings in hippocampal slices and radioligand binding assays in synaptic plasma membranes. We report that beta-L-ODAP is a potent agonist at the non-N-methyl-D-aspartate (NMDA) type of excitatory amino acid receptor. beta-L-ODAP interacts most potently with the quisqualate class of non-NMDA receptors (IC50 = 1.3 microM), less potently with the kainate receptor (IC50 = 17 microM), and very weakly with NMDA receptors. The specificity of this binding was consistent with physiological experiments that demonstrated that beta-L-ODAP-induced depolarizations were potently blocked by the newly identified non-NMDA receptor antagonist, CNQX, but were not affected by the NMDA antagonist D-AP5. These results extend recent studies that have focused on the contribution of NMDA receptors to excitotoxicity and highlight the potential involvement of non-NMDA receptors in excitotoxic-mediated cell death.

This document is available from: http://directlinks.cc/files/muscimol/2542485.pdf

Author List: Bridges R J, Stevens D R, Kahle J S, Nunn P B, Kadri M, Cotman C W

Publication Types: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.

Substances mentioned in the article: Amino Acids, Diamino; Oxadiazoles; Receptors, Amino Acid; Receptors, Cell Surface; oxalyldiaminopropionic acid; Ibotenic Acid; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Quisqualic Acid; Kainic Acid;

Mesh terms: Amino Acids, Diamino/metabolism; Animals; Electrophysiology; Ibotenic Acid/analogs & derivatives; Kainic Acid/metabolism; Male; Oxadiazoles/metabolism; Quisqualic Acid; Rats; Rats, Inbred Strains; Receptors, Amino Acid; Receptors, Cell Surface/metabolism; Structure-Activity Relationship; Synaptic Membranes/metabolism; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid;

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