Neurochemical aspects of the N-methyl-D-aspartate receptor complex.

The N-methyl-D-aspartic acid (NMDA)-sensitive subclass of brain excitatory amino acid receptors is supposed to be a receptor-ionophore complex consisting of at least 3 different major domains including an NMDA recognition site, glycine (Gly) recognition site and ion channel site. Biochemical labeling of the NMDA domain using [3H]L-glutamic acid (Glu) as a radioactive ligand often meets with several critical methodological pitfalls and artifacts that cause a serious misinterpretation of the results. Treatment of brain synaptic membranes with a low concentration of Triton X-100 induces a marked disclosure of [3H]Glu binding sensitive to displacement by NMDA with a concomitant removal of other several membranous constituents with relatively high affinity for the neuroactive amino acid. The NMDA site is also radiolabeled by the competitive antagonist (+/-)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid that reveals possible heterogeneity of the site. The Gly domain is sensitive to D-serine and D-alanine but insensitive to strychnine, and this domain seems to be absolutely required for an opening of the NMDA channels by agonists. The ionophore domain is radiolabeled by a non-competitive type of NMDA antagonist that is only able to bind to the open but not closed channels. The binding of these allosteric antagonists is markedly potentiated by NMDA agonists in a manner sensitive to antagonism by isosteric antagonists in brain synaptic membranes and additionally enhanced by further inclusion of Gly agonists through the Gly domain. Furthermore, physiological and biochemical responses mediated by the NMDA receptor complex are invariably potentiated by several endogenous polyamines, suggesting a novel polyamine site within the complex. At any rate, activation of the NMDA receptor complex results in a marked influx of Ca2+ as well as Na+ ions, which subsequently induces numerous intracellular metabolic alterations that could be associated with neuronal plasticity or excitotoxicity. Therefore, any isosteric and allosteric antagonists would be of great benefit for the therapy and treatment of neurodegenerative disorders with a risk of impairing the acquisition and formation process of memories.