Two classes of N-methyl-D-aspartate recognition sites: Differential distribution and differential regulation by glycine

D. T. Monaghan, H. J. Olverman, L. Nguyen, J. C. Watkins, C. W. Cotman

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The N-methyl-D-aspartate (NMDA) receptor, a subtype of excitatory amino acid receptor, mediates synaptic responses in many regions of the central nervous system. This receptor plays a critical role in the mechanisms of both synaptic plasticity and excitotoxicity. Although these receptors were generally thought to be a single homogeneous receptor population, we report observations indicating that two anatomically distinct forms of the NMDA-receptor complex exist. (i) The distribution of NMDA receptors, as labeled by the NMDA agonist L-[3H]glutamate, differs from that obtained with the radiolabeled antagonist 3H-labeled 3-[(±)2-carboxypiperazine-4-yl]propyl-1-phosphonic acid ([3H]CPP). Relative to L-[3H]glutamate, [3H]CPP binding is low in the striatum and septum and high in the thalamus and inner cerebral cortex. (ii) NMDA antagonists are relatively more potent than agonists at displacing L-[3H]glutamate binding in the thalamus and cerebral cortex; agonists are relatively more potent in the striatum and cerebellum. (iii) Glycine, which potentiates NMDA-receptor responses to glutamate, causes a greater percentage increase in L-[3H]glutamate binding to NMDA receptors in the thalamus and cerebral cortex than in the striatum, septum, and cerebellum. Radiolabeled NMDA-antagonist binding, in contrast, is inhibited by glycine. Thus, as observed for γ-aminobutyric acid type A receptors, NMDA receptors have an agonist-preferring binding-site population and an antagonist-preferring binding site population. These may represent two distinct receptors and/or two interconverting forms. It could be of significant clinical importance if these two sites differ in their response to NMDA.

Original languageEnglish (US)
Pages (from-to)9836-9840
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number24
StatePublished - 1988

ASJC Scopus subject areas

  • General

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