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

Proc Natl Acad Sci U S A. 2000 Apr 25;97(9):4926-31. doi: 10.1073/pnas.97.9.4926.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aging
  • Animals
  • Astrocytes / physiology*
  • Cells, Cultured
  • Cerebellum / growth & development
  • Cerebellum / physiology*
  • D-Amino-Acid Oxidase / metabolism
  • Embryo, Mammalian
  • Glycine*
  • Hippocampus / physiology*
  • In Vitro Techniques
  • Ligands
  • Male
  • Neurons / physiology*
  • Quinoxalines / pharmacology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate / chemistry*
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, N-Methyl-D-Aspartate / physiology*
  • Serine / metabolism*
  • Stereoisomerism

Substances

  • Ligands
  • Quinoxalines
  • Receptors, N-Methyl-D-Aspartate
  • 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline
  • Serine
  • D-Amino-Acid Oxidase
  • Glycine