QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

HOME  |   SEARCH  |   ARCHIVE  |   SUBSCRIBE  |   CONTACT  |   HELP

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

This Article Full Text Full Text (PDF) Submit an eLetter Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Zhang, J. Articles by Yao, W.-D. Search for Related Content PubMed PubMed Citation Articles by Zhang, J. Articles by Yao, W.-D.

 Previous Article  |  Next Article 

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.

---

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

Home  |   Search  |   Archive  |   Subscribe  |   Contact  |   Help