The glycine site of the N-methyl-D-aspartate receptor channel: differences between the binding of HA-966 and of 7-chlorokynurenic acid.

摘要: : The mechanisms of action three different glycinesite antagonists the N-methyl-D-aspartate (NMDA)-receptor channel were analyzed employing [3H]glycine direct binding assays, as well functional glycine- and glutamate-induced uncompetitive blocker assays. latter assays measure apparent opening. All tested, viz., 7-chlorokynurenic acid (7-Cl-KYNA), kynurenic (KYNA), 1-hydroxy-3-aminopyrrolidone-2 (HA-966), inhibited to NMDA receptor in a dose-dependent manner. These also glycine-induced increase accessibility [3H]N-[1-(2-thienyl)cyclohexyl]-piperidine ([3H]TCP) channel. 7-Cl-KYNA KYNA, but not HA-966, completely blocked [3H]TCP, manner similar non-competitive which selective antagonist D-(-)-2-amino-5-phosphonovaleric (AP-5) [3H]TCP binding. inhibitory effects HA-966 AP-5 on overcome when glutamate concentrations increased. Of antagonists, appears be most potent (Ki= 0.4–1.0 μM) glycine antagonist. KYNA was found act at both 40–50 sites. In contrast, 6–17 either domain distinct from sites, tightly associated with latter, or site, according mechanism that 7-Cl-KYNA. results show simultaneous occupancy sites is essential for their activation, support two concepts suggested by previous electrophysiological experiments: co-agonist glutamate, least an M-type allosteric effector (i.e., it increases maximal response without affecting its constant).