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J. Biol. Chem., Vol. 282, Issue 21, 15778-15789, May 25, 2007

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Inhibition of the Dopamine D1 Receptor Signaling by PSD-95^*

Jingping Zhang, Angel Vinuela, Mark H. Neely^¶, Penelope J. Hallett, Seth G. N. Grant^||, Gregory M. Miller, Ole Isacson, Marc G. Caron^¶, and Wei-Dong Yao¹

From the Department of Psychiatry, Harvard Medical School, New England Primate Research Center, Southborough, Massachusetts 01772, the Neuroregeneration Laboratories, McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02478, the ^||Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, United Kingdom, and the ^¶Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710

Dopamine D1 receptors play an important role in movement, reward, and learning and are implicated in a number of neurological and psychiatric disorders. These receptors are concentrated in dendritic spines of neurons, including the spine head and the postsynaptic density. D1 within spines is thought to modulate the local channels and receptors to control the excitability and synaptic properties of spines. The molecular mechanisms mediating D1 trafficking, anchorage, and function in spines remain elusive. Here we show that the synaptic scaffolding protein PSD-95 thought to play a role in stabilizing glutamate receptors in the postsynaptic density, interacts with D1 and regulates its trafficking and function. Interestingly, the D1-PSD-95 interaction does not require the well characterized domains of PSD-95 but is mediated by the carboxyl-terminal tail of D1 and the NH₂ terminus of PSD-95, a region that is recognized only recently to participate in protein-protein interaction. Co-expression of PSD-95 with D1 in mammalian cells inhibits the D1-mediated cAMP accumulation without altering the total expression level or the agonist binding properties of the receptor. The diminished D1 signaling is mediated by reduced D1 expression at the cell surface as a consequence of an enhanced constitutive, dynamindependent endocytosis. In addition, genetically engineered mice lacking PSD-95 show a heightened behavioral response to either a D1 agonist or the psychostimulant amphetamine. These studies demonstrate a role for a glutamatergic scaffold in dopamine receptor signaling and trafficking and identify a new potential target for the modulation of abnormal dopaminergic function.

Received for publication, December 14, 2006 , and in revised form, February 21, 2007.

^* This work was supported by National Institutes of Health Grants RR00168 (to the New England Primate Research Center), by NINDS/National Institutes of Health Grant P50 NS39793 and the Stern, Orchard, and Anti-aging Foundations (to O. I.), and by a National Alliance for Research on Schizophrenia and Depression Young Investigator Award (to W.-D. Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This article was selected as a Paper of the Week.

¹ To whom correspondence should be addressed: Dept. of Psychiatry, Harvard Medical School, New England Primate Research Center, 1 Pine Hill Dr., Southborough, MA 01772. Tel.: 508-624-8106; Fax: 508-786-3317; E-mail: wei-dong_yao{at}hms.harvard.edu.

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