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 [3H]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, [3H]3-(2-carboxypiperazin-4-y1)propyl-1-phosphonate ([3H]CPP) in a dose-dependent fashion, whereas both compounds inhibited NMDA-specific L-[3H]glutamate (agonist) binding. Additionally, both glycine antagonists reduced the binding of [3H]1-[1-(2-thienyl)cyclohexyl]piperidine ([3H]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 [3H]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.
Compton
R P
RP
CNS Diseases Research, G. D. Searle and Company, St. Louis, MO 63198.
Hood
W F
WF
Monahan
J B
JB
D000596:Amino Acids / Q000494:pharmacology; D000598:Amino Acids, Cyclic; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D005971:Glutamates / Q000378:metabolism; D005998:Glycine / Q000031:analogs & derivatives / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D010622:Phencyclidine / Q000031:analogs & derivatives / Q000378:metabolism; D010879:Piperazines / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D013331:Strychnine; D013570:Synaptic Membranes / Q000378:metabolism*
D000596:Amino Acids; D000598:Amino Acids, Cyclic; D005971:Glutamates; D010879:Piperazines; D011760:Pyrrolidinones; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; C016987:1-aminocyclobutanecarboxylic acid; C012058:tenocyclidine; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; C001369:1-hydroxy-3-amino-2-pyrrolidone; D013331:Strychnine; D010622:Phencyclidine; D005998:Glycine