Allosteric modulation of N-methyl-D-aspartate receptors.

In this review we have attempted to describe the basis for current models of the NMDA receptor, and justify the need for the various binding sites that have been proposed. The NMDA receptor is clearly a complex molecule with a number of modulatory sites, any of which may have great functional significance. From the data presented above it is apparent that the NMDA recognition site is closely coupled with the glycine site, and can also be regulated by Zn2+. The glycine site is reciprocally coupled to the NMDA site, and may also be coupled to a divalent-cation site outside the channel. However, the glycine site is insensitive to Zn2+. The Zn2+ site is probably not inside the channel to any degree, but can profoundly affect the ability of NMDA site ligands to operate the channel. However, the determination of reciprocal effects at the Zn2+ site await the development of a suitably potent and selective ligand for this site. Several lines of evidence suggest that the phencyclidine and channel-blocking Mg2+ site are located within the NMDA-operated ion channel. Glutamate, glycine, and Zn2+ alter the binding of ligands to these sites. However, this is most likely to be due to alteration of access of the ligands to their sites rather than a direct allosteric coupling. It does appear that phencyclidine site drugs and Mg2+ bind to separate sites within the channel, and that these separate sites are allosterically coupled. This complex series of interactions, many of which are mediated by endogenous agents, may allow very fine control over the expression of NMDA receptor-mediated synaptic transmission. In addition to these ligand-produced modulatory effects, there may also be covalent modification of the channel by receptor phosphorylation. Furthermore, the voltage sensitivity of some of the effects allows control of NMDA receptor-mediated signaling by alteration of the membrane potential in the postsynaptic cell, which can be achieved in a wide variety of ways. The level of sophistication possible in adjusting the responsiveness of this receptor seems entirely appropriate given its central involvement in a wide variety of fundamental neurobiological events, and underscores the deleterious pathological sequelae of the system tilting out of balance. At the same time, the wide array of possible therapeutic targets raises hopes that it may soon be possible to treat effectively some severely debilitating and currently untreatable diseases.