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The Journal of Neuroscience, March 4, 2009, 29(9):2948-2960; doi:10.1523/JNEUROSCI.4424-08.2009

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Cellular/Molecular
PSD-95 Uncouples Dopamine–Glutamate Interaction in the D₁/PSD-95/NMDA Receptor Complex

Jingping Zhang,¹ Tai-Xiang Xu,¹ Penelope J. Hallett,² Masahiko Watanabe,³ Seth G. N. Grant,⁴ Ole Isacson,² and Wei-Dong Yao¹

¹New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts 01772, ²McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02478, ³Department of Anatomy, Hokkaido University School of Medicine, Sapporo 060-8638, Japan, and ⁴Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, United Kingdom

Correspondence should be addressed to Wei-Dong Yao at the above address. Email: wei-dong_yao{at}hms.harvard.edu

Classical dopaminergic signaling paradigms and emerging studies on direct physical interactions between the D₁ dopamine (DA) receptor and the NMDA glutamate receptor predict a reciprocally facilitating, positive feedback loop. This loop, if not controlled, may cause concomitant overactivation of both D₁ and NMDA receptors, triggering neurotoxicity. Endogenous protective mechanisms must exist. Here, we report that PSD-95, a prototypical structural and signaling scaffold in the postsynaptic density, inhibits D₁–NMDA receptor subunit 1 (NR1) NMDA receptor association and uncouples NMDA receptor-dependent enhancement of D₁ signaling. This uncoupling is achieved, at least in part, via a disinhibition mechanism by which PSD-95 abolishes NMDA receptor-dependent inhibition of D₁ internalization. Knockdown of PSD-95 immobilizes D₁ receptors on the cell surface and escalates NMDA receptor-dependent D₁ cAMP signaling in neurons. Thus, in addition to its role in receptor stabilization and synaptic plasticity, PSD-95 acts as a brake on the D₁–NMDA receptor complex and dampens the interaction between them.

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Received Sept. 13, 2008; revised Jan. 14, 2009; accepted Jan. 22, 2009.

Correspondence should be addressed to Wei-Dong Yao at the above address. Email: wei-dong_yao{at}hms.harvard.edu

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