PSD-95 uncouples dopamine-glutamate interaction in the D1/PSD-95/NMDA receptor complex.
Classical dopaminergic signaling paradigms and emerging studies on direct physical interactions between the D(1) 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 D(1) 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 D(1)-NMDA receptor subunit 1 (NR1) NMDA receptor association and uncouples NMDA receptor-dependent enhancement of D(1) signaling. This uncoupling is achieved, at least in part, via a disinhibition mechanism by which PSD-95 abolishes NMDA receptor-dependent inhibition of D(1) internalization. Knockdown of PSD-95 immobilizes D(1) receptors on the cell surface and escalates NMDA receptor-dependent D(1) cAMP signaling in neurons. Thus, in addition to its role in receptor stabilization and synaptic plasticity, PSD-95 acts as a brake on the D(1)-NMDA receptor complex and dampens the interaction between them.
Zhang
Jingping
J
New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts 01772, USA.
Xu
Tai-Xiang
TX
Hallett
Penelope J
PJ
Watanabe
Masahiko
M
Grant
Seth G N
SG
Isacson
Ole
O
Yao
Wei-Dong
WD
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D000242:Cyclic AMP / Q000502:physiology; D000076122:Disks Large Homolog 4 Protein; D004298:Dopamine / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D018698:Glutamic Acid / Q000502:physiology*; D051528:Guanylate Kinases; D006801:Humans; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D016180:Lentivirus Infections / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D010957:Plasmids; D011869:Radioligand Assay; D017447:Receptors, Dopamine D1 / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection
D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D000242:Cyclic AMP; D051528:Guanylate Kinases; D004298:Dopamine