Functional Regulation of Dopamine D(3) Receptor through Interaction with PICK1

PICK1, a PDZ domain-containing protein, is known to increase the reuptake activities of dopamine transporters by increasing their expressions on the cell surface. Here, we report a direct and functional interaction between PICK1 and dopamine D(3) receptors (D(3)R), which act as autoreceptors to negatively regulate dopaminergic neurons. PICK1 colocalized with both dopamine D(2) receptor (D(2)R) and D(3)R in clusters but exerted different functional influences on them. The cell surface expression, agonist affinity, endocytosis, and signaling of D(2)R were unaffected by the coexpression of PICK1. On the other hand, the surface expression and tolerance of D(3)R were inhibited by the coexpression of PICK1. These findings show that PICK1 exerts multiple effects on D(3)R functions.