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

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

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  • 1Departments of Neuroscience, Pharmacology and Molecular Sciences and Psychiatry, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205-21185, USA.


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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