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

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

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N-Methyl-D-Aspartate Receptors
Glycine
Serine
Ligands
D-Amino-Acid Oxidase
Enzymes
Synaptic Transmission
Synapses
Glutamic Acid
Calcium

ASJC Scopus subject areas

  • Genetics
  • General

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D-serine is an endogenous ligand for the glycine site of the N-methyl-D- aspartate receptor. / Mothet, Jean Pierre; Parent, Angèle T.; Wolosker, Herman; Brady, Roscoe O.; Linden, David J; Ferris, Christopher D.; Rogawski, Michael A.; Snyder, Solomon H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 97, No. 9, 25.04.2000, p. 4926-4931.

Research output: Contribution to journalArticle

Mothet, Jean Pierre ; Parent, Angèle T. ; Wolosker, Herman ; Brady, Roscoe O. ; Linden, David J ; Ferris, Christopher D. ; Rogawski, Michael A. ; Snyder, Solomon H. / D-serine is an endogenous ligand for the glycine site of the N-methyl-D- aspartate receptor. In: Proceedings of the National Academy of Sciences of the United States of America. 2000 ; Vol. 97, No. 9. pp. 4926-4931.
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AU - Mothet, Jean Pierre

AU - Parent, Angèle T.

AU - Wolosker, Herman

AU - Brady, Roscoe O.

AU - Linden, David J

AU - Ferris, Christopher D.

AU - Rogawski, Michael A.

AU - Snyder, Solomon H

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AB - 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.

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