Dopamine D1 receptor-dependent trafficking of striatal NMDA glutamate receptors to the postsynaptic membrane

Recent work has shown substantial alterations in NMDA receptor subunit expr ession, assembly, and phosphorylation in the dopamine-depleted striatum of a rodent 6-hydroxydopamine model of Parkinson's disease. These modification s are hypothesized to result from the trafficking of NMDA receptors between subcellular compartments. Here we show that in rat striatal tissues the NR 2A and NR2B subunits in the synaptosomal membrane, and not those in the lig ht membrane and synaptic vesicle-enriched compartments, are tyrosine phosph orylated. The dopamine D1 receptor agonist SKF-82958 produces (1) an increa se in NR1, NR2A, and NR2B proteins in the synaptosomal membrane fraction; ( 2) a decrease in NR1, NR2A, and NR2B proteins in the light membrane and syn aptic vesicle-enriched fractions; and (3) an increase in the tyrosine phosp horylation of NR2A and NR2B in the synaptosomal membrane compartment. The p rotein phosphatase inhibitor pervanadate reproduces the alterations in subc ellular distribution and phosphorylation, whereas the effects of the dopami ne D1 receptor agonist are blocked by genistein, a protein tyrosine kinase inhibitor. Dopamine D1 receptor agonist treatment does not change the subce llular distribution of the AMPA receptor subunits GluR1 or GluR2/3 in the s triatum and has no effect on cortical or cerebellar NMDA receptor subunits. These data reveal a rapid dopamine D1 receptor- and tyrosine kinase-depend ent trafficking of striatal NMDA receptors between intracellular and postsy naptic sites. The subcellular trafficking of striatal NMDA receptors may pl ay a significant role both in the pathogenesis of Parkinson's disease and i n the development of adverse effects of chronic dopaminergic therapy in par kinsonian patients.