GLUTAMATE AND GLYCINE DECREASE THE AFFINITY OF [H-3] MK-801 BINDING IN THE PRESENCE OF MG2+

The NMDA receptor is coupled to a cation-selective ion channel, which has been implicated in important brain functions such as long-term pot entiation and burst firing, and in neuronal death associated with stro ke and epilepsy. We have investigated the binding properties of [H-3]M K-801, which binds selectively to the open state of the NMDA channel, at physiological concentrations of Mg2+ in membrane preparations of th e rat cerebral cortex. Glutamate and glycine were found to enhance [H- 3]MK-801 binding at low concentrations and inhibit [H-3]MK-801 binding at high concentrations. The inhibition of [H-3]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 affi nity of [H-3]MK-801 binding sites within activated NMDA channels, in t he presence of Mg2+. This decrease in [H-3]MK-801 affinity may corresp ond to a decreased affinity of the site where Mg2+ causes a voltage-de pendent block of the NMDA channel.