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- Title
PSD-95 Uncouples Dopamine-Glutamate Interaction in the D<sub>1</sub>/PSD-95/NMDA Receptor Complex.
- Authors
Jingping Zhang; Tai-Xiang Xu; Hallett, Penelope J.; Watanabe, Masahiko; Grant, Seth G. N.; Isacson, Ole; Wei-Dong Yao
- Abstract
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)NMDAreceptor association and uncouplesNMDAreceptor-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.
- Subjects
DOPAMINERGIC mechanisms; DOPAMINE receptors; GLUTAMIC acid; NEUROTOXICOLOGY; PROTEIN receptors
- Publication
Journal of Neuroscience, 2009, Vol 29, Issue 9, p2948
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.4424-08.2009