N-メチル-D-アスパラギン酸シグナル受容に関する薬理学的研究

抄録

A series of investigations has been made to analyze the receptive mechanisms for signals mediated by an N-methyl D-aspartic acid (NMDA)-sensitive subclass of brain excitatory amino acid receptors. Treatment of synaptic membranes with a low concentration of Triton X-100 induced a drastic disclosure of NMDA-sensitive [³H] glutamic acid binding without affecting the NMDAinsensitive populations. In these Triton-treated membranes, binding of [³H] glycine (Gly) was displaced by D-serine and D-alanine, but not by strychnine. These membrane preparations were also useful for detecting the binding of noncompetitive blockers to open NMDA channels in a manner highly sensitive to potentiation by NMDA, Gly and the polyamine spermidine. Comparative studies on the binding of agonist and antagonist ligands in different central regions suggested the possible heterogeneity of the NMDA, Gly and ionophore domains. By screening more than 1000 compounds, the binding of noncompetitive blockers was completely abolished by the addition of 6, 7dichloroquinoxaline-2, 3-dione, which was revealed to be a selective antagonist for the Gly domain. Binding studies using the aforementioned radioligands gave rise to the idea that both reduced and oxidized glutathione could be endogenous agonists for the NMDA domain. An i.c.v. injection of NMDA led to a marked potentiation of DNA binding activities of particular transcription factors in a manner sensitive to antagonism by antagonists at the respective domains. These results suggest that NMDA signals are indeed transduced from cell surfaces into nuclei to express nuclear transcription factors through the NMDA-sensitive subclass that is a receptor ionophore complex consisting of at least 4 different constituents including the NMDA, Gly, polyamine and ionophore domains.