Schild plot analysis of glycine and kynurenic acid at the N-methyl-D-aspartate excitatory amino acid receptor.
Glycine enhanced the N-methyl-D-aspartate (NMDA)-stimulated sodium flux in rat hippocampal slides in a concentration-dependent manner. The potentiation by glycine was apparently not competitive to NMDA with a maximal effect of about 50% enhancement at approximately 150 microM glycine. Glycine also reversed the kynurenic acid inhibition of NMDA-stimulated sodium flux, increasing flux two-fold. In the absence of glycine, the kynurenic acid inhibition of NMDA-stimulated sodium flux appeared not competitive to NMDA, with a Schild plot slope of 0.6 +/- 0.1, significantly less than 1 (P less than 0.05). Addition of 100 microM glycine gave a Schild plot slope of 1.0 +/- 0.3, classically defining competitive inhibition. However, the pKb of 4.5 obtained from the x intercept gives an inaccurate estimate of the affinity of kynurenic acid for the NMDA recognition site since glycine is present. Addition of 400 microM glycine resulted in a Schild plot slope of 1.9 +/- 0.2. By varying the concentrations of glycine, we have apparently reproduced a portion of the theoretical set of curves for various ratios of affinities of the antagonist for the agonist recognition site and a second site. These results support a model where glycine modulates NMDA receptor function and where kynurenic acid acts both as a competitive antagonist to NMDA and at a second site from which it is displaced by glycine.
Pullan
L M
LM
Searle CNS Diseases Research, St. Louis, MO 63198.
Cler
J A
JA
D000818:Animals; D005998:Glycine / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D007736:Kynurenic Acid / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000502:physiology*; D012964:Sodium / Q000502:physiology*
D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D012964:Sodium; D007736:Kynurenic Acid; D005998:Glycine