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PMID: 10781100 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

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

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 97 ·No. 9 ·2000-04-25 ·Pages 4926-31

Mothet JP, Parent AT, Wolosker H, Brady RO, Linden DJ, Ferris CD, Rogawski MA, Snyder SH

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.

MeSH Terms
Aging Animals Astrocytes/physiology Cells, Cultured Cerebellum/growth & development,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,drug effects,physiology Serine/metabolism Stereoisomerism
Chemicals
Ligands Quinoxalines Receptors, N-Methyl-D-Aspartate 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline Serine D-Amino-Acid Oxidase Glycine
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Mothet J P
Departments of Neuroscience, Pharmacology and Molecular Sciences and Psychiatry, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205-21185, USA.
Parent A T
Wolosker H
Brady R O
Linden D J
Ferris C D
Rogawski M A
Snyder S H
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.97.9.4926
Published
2000-04-25
Pages
4926-31
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC18334
Subset
IM
Grants
NIDA NIH HHS · DA00074 · United States
NIMH NIH HHS · R37 MH018501 · United States
NIMH NIH HHS · R01 MH018501 · United States
NIDA NIH HHS · K05 DA000074 · United States
NIMH NIH HHS · MH-18501 · United States
External Links
PubMed source DOI: 10.1073/pnas.97.9.4926 PMC Full Text View journal details
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