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

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

^*Departments of Neuroscience, Pharmacology and Molecular Sciences and Psychiatry, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205-21185; and ^§Epilepsy Research Branch, National Institutes of Neurological Disorders and Stroke, National Institute of Health, 10 Center Drive Room 5N-250 MSC 1408, Bethesda, MD 20892-1408

Contributed by Solomon H. Snyder

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.

Footnotes

↵ † Present address: Laboratoire de Neurobiologie Cellulaire et Moléculaire, CNRS UPR 9040, 1, avenue de la Terrasse, 91198 Gif-sur-Yvette, France.
↵ ‡ J.-P.M. and A.T.P. contributed equally to this work.
↵ ¶ Present address: Department of Neurobiology, Pharmacology and Physiology, The University of Chicago, 947 East 58th Street, Chicago, IL 60637.
↵ ‖ To whom reprint requests should be addressed. E-mail: ssnyder{at}bs.jhmi.edu.
Abbreviations:

NMDA,

N-methyl-d-aspartate;

DAAOX,

d-amino acid oxidase;

NBQX,

2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline;

CPP,

3-[(±)-2-carboxypiperazin-4-yl]propyl-1-phosphonate;

AMPA,

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid;

NOS,

nitric-oxide synthase