PSD-95 uncouples dopamine-glutamate interaction in the D ₁/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.