D-serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor.
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.
Mothet
J P
JP
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
AT
Wolosker
H
H
Brady
R O
RO
Linden
D J
DJ
Ferris
C D
CD
Rogawski
M A
MA
Snyder
S H
SH
D000375:Aging; D000818:Animals; D001253:Astrocytes / Q000502:physiology*; D002478:Cells, Cultured; D002531:Cerebellum / Q000254:growth & development / Q000502:physiology*; D003605:D-Amino-Acid Oxidase / Q000378:metabolism; D004622:Embryo, Mammalian; D005998:Glycine; D006624:Hippocampus / Q000502:physiology*; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D009474:Neurons / Q000502:physiology*; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry* / Q000187:drug effects / Q000502:physiology*; D012694:Serine / Q000378:metabolism*; D013237:Stereoisomerism
D008024:Ligands; D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; D012694:Serine; D003605:D-Amino-Acid Oxidase; D005998:Glycine