d -Serine is an endogenous ligand for the glycine site of the N -methyl- d -aspartate receptor

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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.