PSD-95 regulates D1 dopamine receptor resensitization, but not receptor-mediated Gs-protein activation.

The present study aims to define the role of postsynaptic density (PSD)-95 in the regulation of dopamine (DA) receptor function. We found that PSD-95 physically associates with either D(1) or D(2) DA receptors in co-transfected HEK-293 cells. Stimulation of DA receptors altered the association between D(1) receptor and PSD-95 in a time-dependent manner. Functional assays indicated that PSD-95 co-expression did not affect D(1) receptor-stimulated cAMP production, Gs-protein activation or receptor desensitization. However, PSD-95 accelerated the recovery of internalized membrane receptors by promoting receptor recycling, thus resulting in enhanced resensitization of internalized D(1) receptors. Our results provide a novel mechanism for regulating DA receptor recycling that may play an important role in postsynaptic DA functional modulation and synaptic neuroplasticity.