FUNCTIONAL-CHARACTERIZATION OF HUMAN N-METHYL-D-ASPARTATE SUBTYPE 1A 2D RECEPTORS/

The human NMDAR2D subunit was cloned, and the pharmacological properti es of receptors resulting from injection of transcripts encoding human NMDAR1A and NMDAR2D subunits in Xenopus oocytes were characterized by profiling NMDA receptor agonists and antagonists. We found that gluta mate, NMDA, glycine, and D-serine were significantly more potent on hN MDAR1A/2D than on hNMDAR1A/2A or hNMDAR1A/2B. Also, the potencies of N MDA and glycine were higher for hNMDAR1A/2D than for hNMDAR1A/2C. Ifen prodil was more potent at hNMDAR1A/ 2B than at hNMDAR1A/2D, whereas 5, 7-dichlorokynurenate was more potent at hNMDAR1A/2A than at hNMDAR1A/ 2D. As measured in transiently transfected human embryonic kidney 293 cells, the maximal inward current in the presence of external Mg2+ occ urred at -40 mV, and full block was not observed at negative potential s. Kinetic measurements revealed that the higher affinity of hNMDAR1A/ 2D for both glutamate and glycine relative to hNMDAR1A/2A and hNMDA1A/ 2B can be explained by slower dissociation of each agonist from hNMDAR 1A/2D. The hNMDAR1A/2D combination represents a pharmacologically and functionally distinct receptor subtype and may constitute a potentiall y. important target for therapeutic agents active in the human CNS.