Interactions Between the Glutamate and Glycine Recognition Sites of the N-Methyl-d-Aspartate Receptor from Rat Brain, as Revealed from Radioligand Binding Studies |
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Authors: | Sarah Grimwood Geraint J C Wilde Alam C Foster |
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Institution: | Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, England |
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Abstract: | Abstract: The N-methyl-d -aspartate (NMDA) receptor possesses two distinct amino acid recognition sites, one for glutamate and one for glycine, which appear to be allosterically linked. Using rat cortex/hippocampus P2 membranes we have investigated the effect of glutamate recognition site ligands on 3H]glycine (agonist) and (±)4-trans-2-car-boxy-5,7-dichloro-4-3H]phenylaminocarbonylamino-1,2,3,4-tetrahydroquinoline (3H]l -689,560; antagonist) binding to the glycine site and the effect of glycine recognition site ligands on l -3H]glutamate (agonist), dl -3-(2-carboxypiperazin-4-yl)-3H]propyl-1 -phosphonate (3H]-CPP; “C-7” antagonist), and cis-4-phosphonomethyl-2-3H]piperidine carboxylate (3H]CGS-19755; “C-5” antagonist) binding to the glutamate site. “C-7” glutamate site antagonists partially inhibited 3H]l -689,560 binding but had no effect on 3H]glycine binding, whereas “C-5” antagonists partially inhibited the binding of both radioligands. Glycine, d -serine, and d -cycloserine partially inhibited 3H]CGS-19755 binding but had little effect on l -3H]-glutamate or 3H]CPP binding, whereas the partial agonists (+)-3-amino-1-hydroxypyrrolid-2-one (+)-HA-966], 3R-(+)cis-4-methyl-HA-966 (l -687,414), and 1-amino-1-carboxycyclobutane all enhanced 3H]CPP binding but had no effect on 3H]CGS-19755 binding, and (+)-HA-966 and l -687,414 inhibited l -3H]glutamate binding. The association and dissociation rates of 3H]l -689,560 binding were decreased by CPP and d -2-amino-5-phosphonopentanoic acid (“C-5”). Saturation analysis of 3H]l -689,560 binding carried out at equilibrium showed that CPP had little effect on the affinity or number of 3H]l -689,560 binding sites. These results indicate that complex interactions occur between the glutamate and glycine recognition sites on the NMDA receptor. In addition, mechanisms other than allosterism may underlie some effects, and the possibility of a steric interaction between CPP and 3H]l -689,560 is discussed. |
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Keywords: | Glycine Glutamate NMDA receptor [3H]l-689 560 binding Allosteric interaction |
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