Multiple sites for the regulation of the N-methyl-D-aspartate receptor

The N-methyl-D-aspartate (NMDA) receptor consists of a recognition site for NMDA, a cation-selective ion channel, and binding sites for glycine, Zn²⁺, and phencyclidine-like compounds. In addition, the channel can be blocked by Mg²⁺. We have studied the NMDA receptor using the potent and specific phencyclidine-like compound [³H]MK-801. Drugs that bind to the NMDA, glycine, Zn²⁺, and Mg²⁺ recognition sites profoundly affect both the association and the dissociation rate of [³H]MK-801. NMDA-like agonists, glycine, and Mg²⁺ all increase the rates of association and dissociation of [³H]MK-801, whereas the NMDA antagonists AP5 and Zn²⁺ decrease these rates. These data allow the construction of a model of drug interaction at the NMDA receptor that is based on the binding of MK-801 within the NMDA-operated channel. Using this model it is possible to clearly distinguish between drug action at any of the five binding sites proposed.