Glutamate and glycine decrease the affinity of [ 3H]MK-801 binding in the presence of Mg 2+

Abstract

The NMDA receptor is coupled to a cation-selective ion channel, which has been implicated in important brain functions such as long-term potentiation and burst firing, and in neuronal death associated with stroke and epilepsy. We have investigated the binding properties of [ 3H]MK-801, which binds selectively to the open state of the NMDA channel, at physiological concentrations of Mg 2+ in membrane preparations of the rat cerebral cortex. Glutamate and glycine were found to enhance [ 3H]MK-801 binding at low concentrations and inhibit [ 3H]MK-801 binding at high concentrations. The inhibition of [ 3H]MK-801 binding was due to an enhancement of the dissociation rate constant and was reversed by competitive glutamate and glycine antagonists. These findings could be explained by a glutamate- and glycine-induced decrease in the affinity of [ 3H]MK-801 binding sites within activated NMDA channels, in the presence of Mg 2+. This decrease in [ 3H]MK-801 affinity may correspond to a decreased affinity of the site where mg 2+ causes a voltage-dependent block of the NMDA channel.