Prolonged enhancement of AP-1 DNA binding by blockade of glutamate uptake in cultured neurons.

Abstract

Prolonged blockade of glutamate reuptake by the specific inhibitor of glutamate transporters, L-transpyrrolidine-2,4-dicarboxylate (PDC), produces a dramatic decrease in NMDA-induced neurotoxicity in cerebellar granule cell cultures, and is accompanied by a down-regulation of NMDA receptors. We now report that cultured cerebellar granule cells treated with 100 microM PDC for 1, 2, 4, 8, 16 and 24h, respectively, show increased AP-1 DNA-binding activity as measured by electrophoretic mobility shift assay. This effect was blocked by the NMDA receptor antagonist, CGP 37849, indicative of a pivotal role of NMDA receptors in the PDC-evoked enhancement of AP-1 DNA-binding. Our results suggest that AP-1 may be involved in the transcriptional regulation of neuronal adaptation initiated by prolonged inhibition of glutamate reuptake.