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The Journal of Neuroscience, April 26, 2006, 26(17):4690-4700; doi:10.1523/JNEUROSCI.0792-06.2006

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Cellular/Molecular
Dopamine D₁ Activation Potentiates Striatal NMDA Receptors by Tyrosine Phosphorylation-Dependent Subunit Trafficking

Penelope J. Hallett, Robert Spoelgen, Bradley T. Hyman, David G. Standaert, and Anthone W. Dunah

MassGeneral Institute for Neurodegenerative Disease, Harvard Medical School and Massachusetts General Hospital, Charlestown, Massachusetts 02129

Correspondence should be addressed to Dr. Anthone W. Dunah, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, 114 16th Street, B114-2125, Charlestown, MA 02129. Email: dunah{at}helix.mgh.harvard.edu

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.

Key words: glutamate receptors; NMDA receptors; dopamine receptors; striatal neurons; tyrosine phosphorylation; receptor trafficking

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Received Dec. 9, 2005; revised March 24, 2006; accepted March 27, 2006.

Correspondence should be addressed to Dr. Anthone W. Dunah, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, 114 16th Street, B114-2125, Charlestown, MA 02129. Email: dunah{at}helix.mgh.harvard.edu

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