Functional Comparison of d-Serine and Glycine in Rodents: The Effect on Cloned NMDA Receptors and the Extracellular Concentration


Address correspondence and reprint requests to Dr. K. Wada at Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi, Kodaira, Tokyo 187, Japan.


Abstract: We compared the activity of free d-Ser on the potentiation of cloned NMDA receptors with that of Gly by using a Xenopus oocyte expression system. The extracellular concentration of free d-Ser and Gly was further studied by means of microdialysis. The ED50 values of d-Ser were three to four times lower than those of Gly in any combination of ε1, ε2, ε3, or ε4 and ζ1. Site-directed mutagenesis of ζ1 subunits revealed that some aromatic residues necessary for the action of Gly affected the ED50 value of d-Ser. This result showed that the residues play crucial roles in the action of d-Ser. In vivo microdialysis of rodent brain revealed that the extracellular concentration of free d-Ser in the frontal cortex (6.5 µM) was high enough to saturate the Gly site on the NMDA receptor, but that in the cerebellum was not. These findings suggest that d-Ser is a candidate of the endogenous potentiator of the NMDA receptor in the rodent frontal cortex.