EVIDENCE FOR A FUNCTIONAL COUPLING OF THE NMDA AND GLYCINE RECOGNITION SITES IN SYNAPTIC PLASMA-MEMBRANES

Activation of the N-methyl-D-aspartate (NMDA) receptor complex is subject to modulation via interactions at a coupled [H-3]glycine recognition site in rat brain synaptic plasma membranes (SPM). We examined the effect of the potent and specific glycine site antagonists, 1-hydroxy-3-amino-2-pyrrolidone (HA-966) and 1-aminocyclobutane-1-carboxylate (ACBC), on the NMDA recognition site. These glycine analogs were found to significantly stimulate the binding of the competitive NMDA antagonist, [H-3]-(2-carboxypiperazin-4-yl)propyl-1-phosphonate ([H-3]CPP) in a dose-dependent fashion, whereas both compounds inhibited NMDA-specific L-[H-3]glutamate (agonist) binding. Additionally, both glycine antagonists reduced the binding of [H-3]1-[1-(2-thienyl)cyclohexyl]piperidine ([H-3]TCP) to SPM, a functional assessment of activation of the NMDA receptor-channel complex. The glycine site agonists, glycine and serine reversed these effects in a dose-dependent manner, with the serine reversal being stereospecific for D-serine. The relative potencies of these compounds in reversing the glycine antagonist effects on the NMDA recognition site corresponded with their ability to competitively displace strychnine-insensitive [H-3]glycine binding. These results provide evidence for a functional coupling between the glycine and NMDA recognition sites and further, may provide a mechanism by which compounds interacting at the glycine recognition site may modulate NMDA receptor activity.