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.
Reynolds
I J
IJ
Department of Pharmacological and Physiological Sciences, University of Chicago, Illinois 60637.
Miller
R J
RJ
D000818:Animals; D001665:Binding Sites; D003986:Dibenzocycloheptenes / Q000378:metabolism; D016291:Dizocilpine Maleate; D066298:In Vitro Techniques; D008274:Magnesium / Q000494:pharmacology; D008954:Models, Biological; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D015032:Zinc / Q000494:pharmacology
D003986:Dibenzocycloheptenes; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D016291:Dizocilpine Maleate; D008274:Magnesium; D015032:Zinc