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)
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.
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;