Dopamine D1 activation potentiates striatal NMDA receptors by tyrosine phosphorylation-dependent subunit trafficking.
Interactions between dopaminergic and glutamatergic afferents in the striatum are essential for motor learning and the regulation of movement. An important mechanism for these interactions is the ability of dopamine, through D1 receptors, to potentiate NMDA glutamate receptor function. Here we show that, in striatal neurons, D1 receptor activation leads to rapid trafficking of NMDA receptor subunits, with increased NR1 and NR2B subunits in dendrites, enhanced coclustering of these subunits with the postsynaptic density scaffolding molecule postsynaptic density-95, and increased surface expression. The dopamine D1 receptor-mediated NMDA receptor trafficking is blocked by an inhibitor of tyrosine kinases. Blockers of tyrosine phosphatases also induce NMDA subunit trafficking, but this effect is nonselective and alters both NR2A- and NR2B-containing receptors. Furthermore, tyrosine phosphatase inhibition leads to the clustering of tyrosine-phosphorylated NR2B subunit along dendritic shafts. Our findings reveal that D1 receptor activation can potentiate striatal NMDA subunit function by directly promoting the surface insertion of the receptor complexes. This effect is regulated by the reciprocal actions of protein tyrosine phosphatases and tyrosine kinases. Modification of these pathways may be a useful therapeutic target for Parkinson's disease and other basal ganglia disorders in which abnormal function of striatal NMDA receptors contributes to the symptoms of the diseases.
Hallett
Penelope J
PJ
MassGeneral Institute for Neurodegenerative Disease, Harvard Medical School, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.
Spoelgen
Robert
R
Hyman
Bradley T
BT
Standaert
David G
DG
Dunah
Anthone W
AW
D000818:Animals; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000378:metabolism*; D010766:Phosphorylation; D021122:Protein Subunits; D021381:Protein Transport / Q000502:physiology; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D014018:Tissue Distribution; D014443:Tyrosine / Q000378:metabolism*
D021122:Protein Subunits; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; D014443:Tyrosine; D017027:Protein Tyrosine Phosphatases