Interaction of 6-cyano-7-nitroquinoxaline-2,3-dione with the N-methyl-D-aspartate receptor-associated glycine binding site.

Details

Serval ID
serval:BIB_72D6ADDE0B73
Type
Article: article from journal or magazin.
Collection
Publications
Title
Interaction of 6-cyano-7-nitroquinoxaline-2,3-dione with the N-methyl-D-aspartate receptor-associated glycine binding site.
Journal
Molecular pharmacology
Author(s)
Lester R.A., Quarum M.L., Parker J.D., Weber E., Jahr C.E.
ISSN
0026-895X (Print)
ISSN-L
0026-895X
Publication state
Published
Issued date
05/1989
Peer-reviewed
Oui
Volume
35
Number
5
Pages
565-570
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
Publication Status: ppublish
Abstract
The interaction of newly described antagonist of the non-NMDA glutamate receptor 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) with the glycine site of the NMDA receptor complex has been investigated. In whole-cell patch recordings from hippocampal neurons maintained in culture, currents induced by N-methyl-D-aspartate (NMDA) were dependent on extracellular glycine. Responses to both NMDA (30 microM) and kainate (20 microM) were reduced by CNQX (10-30 microM). The antagonism by CNQX of NMDA, but not kainate, receptor-mediated responses could be reversed by increasing the concentration of glycine in the external medium. Glycine concentration-response curves constructed in the presence of 30 microM NMDA were shifted to the right by CNQX, suggesting that CNQX was competing with glycine for the glycine binding site. However, even at high concentrations of glycine (300 microM) the maximal NMDA current obtained in the presence of CNQX (10-30 microM) was not restored to control levels. Because CNQX had no effect on responses produced by supramaximal concentrations of NMDA (500 microM) and glycine (300 microM), it is suggested that CNQX also interacts with the NMDA recognition site. The antagonism of currents induced by NMDA was not dependent on the membrane potential, and the rapid onset and offset of the block suggested that there was little or no use dependence. Radioligand binding experiments were performed using [3H]glycine to label the strychnine-insensitive glycine regulatory site of the NMDA receptor complex in guinea pig brain frontal cortex membranes. CNQX displaced [3H]glycine binding in a concentration-dependent manner (IC50 = 5.7 microM). Scatchard analysis of the inhibition showed a decrease in the affinity (increase in Kd) of [3H]glycine binding, but no change in the number of binding sites (Bmax) in the presence of 5 microM CNQX, suggesting a competitive interaction. These data provide evidence that CNQX antagonizes NMDA receptor-mediated responses by competing with glycine for a modulatory site associated with the NMDA receptor complex. Furthermore, the results indicate that CNQX may not be as selective an antagonist for non-NMDA receptors as initially described, although its selectivity will depend on the concentration of the NMDA receptor ligand and may be enhanced by increasing the extracellular concentration of glycine.
Keywords
6-Cyano-7-nitroquinoxaline-2,3-dione, Animals, Aspartic Acid/analogs & derivatives, Aspartic Acid/pharmacology, Cells, Cultured, Glycine/metabolism, Glycine/pharmacology, N-Methylaspartate, Quinoxalines/pharmacology, Rats, Receptors, Glycine, Receptors, N-Methyl-D-Aspartate, Receptors, Neurotransmitter/drug effects
Pubmed
Web of science
Create date
19/11/2007 11:33
Last modification date
14/04/2023 11:53
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