Allosteric interactions and modulator requirement for NMDA receptor function

Abstract

Activation of NMDA receptors by glutamate, glycine and spermine was assessed using non-equilibrium [ 3H]dizocilpine binding. Glutamate and glycine mutually increased their efficacies and affinities to stimulate [ 3H]dizocilpine binding, which were further increased by spermine. Enhancement curves by glycine in the presence of increasing concentrations of the glycine antagonist 7-chlorokynurenate revealed that spermine markedly increased the affinity of glycine but not that of 7-chlorokynurenate, and that glycine was also required for [ 3H]dizocilpine binding in the presence of spermine. Spermine had a biphasic effect on [ 3H]dizocilpine binding, with a stimulatory phase followed by an inhibitory phase. The potency of spermine for both phases was increased by glutamate, but not by glycine. These observations indicate that there are positive cooperative interactions between the glutamate, the glycine and the stimulatory and inhibitory polyamine sites of the NMDA receptor. Moreover, glutamate and glycine, but not spermien, are required to activate the receptor.