D-serine is an endogenous ligand for the glycine site of the N-methyl-D- aspartate receptor

Jean Pierre Mothet, Angèle T. Parent, Herman Wolosker, Roscoe O. Brady, David J. Linden, Christopher D. Ferris, Michael A Rogawski, Solomon H. Snyder

Research output: Contribution to journalArticle

835 Scopus citations

Abstract

Functional activity of N-methyl-D-aspartate (NMDA) receptors requires both glutamate binding and the binding of an endogenous coagonist that has been presumed to be glycine, although D-serine is a more potent agonist. Localizations of D-serine and it biosynthetic enzyme serine racemase approximate the distribution of NMDA receptors more closely than glycine. We now show that selective degradation of D-serine with D-amino acid oxidase greatly attenuates NMDA receptor-mediated neurotransmission as assessed by using whole-cell patch-clamp recordings or indirectly by using biochemical assays of the sequelae of NMDA receptor-mediated calcium flux. The inhibitory effects of the enzyme are fully reversed by exogenously applied D-serine, which by itself did not potentiate NMDA receptor-mediated synaptic responses. Thus, D-serine is an endogenous modulator of the glycine site of NMDA receptors and fully occupies this site at some functional synapses.

Original languageEnglish (US)
Pages (from-to)4926-4931
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume97
Issue number9
DOIs
StatePublished - Apr 25 2000
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • General

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