Desensitization of N-methyl-D-aspartate receptors in neurons dissociated from adult rat hippocampus

Desensitization of the N-methyl-D-aspartate (NMDA) receptor-channel complex was studied in isolated rat hippocampal neurons using a fast drug application system. 1) Desensitization rate was slower at more negative membrane potentials and when external [Ca²⁺] was lowered. 2) In the presence of 10 μM glycine, 2-amino-5-phosphonovalerate neither induced desensitization nor prevented recovery from it. 3) Preincubation in 500 μM aspartate or 10 μM glycine alone elicited desensitization only weakly or not at all. 4) Aspartate appeared to bind at its receptor site in the absence of glycine, and vice versa. It is proposed that, for the NMDA receptor, channel opening is necessary for the occurrence of desensitization and, thus, that desensitization involves structural changes in the channel-lining section of the protein rather than the glycine or NMDA binding sites.