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Dopamine D1-Dependent Trafficking of Striatal N-Methyl-D-aspartate Glutamate Receptors Requires Fyn Protein Tyrosine Kinase but Not DARPP-32

Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Center for Aging, Genetics, and Neurodegeneration, Charlestown, Massachusetts (A.W.D., A.C.S., E.B., M.A.S., D.G.S.); and Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York (A.A.F.)

Interactions between dopaminergic and glutamatergic systems in the striatum are thought to underlie both the symptoms and adverse effects of treatment of Parkinson's disease. We have previously reported that activation of the dopamine D1 receptor triggers a rapid redistribution of striatal N-methyl-D-aspartate (NMDA) receptors between intracellular and postsynaptic sub-cellular compartments. To unravel the signaling pathways underlying this trafficking, we studied mice with targeted disruptions of either the gene that encodes the dopamine- and cAMP-regulated phosphoprotein (DARPP-32), a potent and selective inhibitor of protein phosphatase-1, or the protein tyrosine kinase Fyn. In striatal tissue from DARPP-32-depleted mice, basal tyrosine and serine phosphorylation of striatal NMDA receptor subunits NR1, NR2A, and NR2B was normal, and activation of dopamine D1 receptors with the agonist SKF-82958 [(±)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetra-hydro-1H-benzazepine] produced redistribution of NMDA receptors from vesicular compartments (P3 and LP2) to synaptosomal membranes (LP1). In the Fyn knockout mice, basal tyrosine phosphorylation of NR2A and NR2B was drastically reduced, whereas serine phosphorylation of these NMDA subunits was unchanged. In the Fyn knockout mice, the dopamine D1 receptor agonist failed to induce subcellular redistribution of NMDA receptors. In addition, Fyn-depleted mice lesioned with 6-hydroxydopamine also failed to exhibit L-DOPA-induced behavioral sensitization, but this may be caused, at least in part, by resistance of these mice to the neurotoxic lesion. These findings suggest a novel mechanism for the trafficking of striatal NMDA receptors by signaling pathways that are independent of DARPP-32 but require Fyn protein tyrosine kinase. Strategies that prevent NMDA receptor subcellular redistribution through inhibition of Fyn kinase may prove useful in the treatment of Parkinson's disease.

Address correspondence to: Dr. David G. Standaert, Department of Neurology, Massachusetts General Hospital, Center for Aging, Genetics, and Neurodegeneration, 114 16th Street, CNY114-2004, Charlestown, MA 02129. E-mail: standaert{at}helix.mgh.harvard.edu

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