Calcyon forms a novel ternary complex with dopamine D₁ receptor through PSD-95 protein and plays a role in dopamine receptor internalization

Calcyon, once known for interacting directly with the dopamine D ₁ receptor (D₁DR), is implicated in various neuropsychiatric disorders including schizophrenia, bipolar disorder, and attention deficit hyperactivity disorder. Although its direct interaction with D₁DR has been shown to be misinterpreted, it still plays important roles in D₁DR signaling. Here, we found that calcyon interacts with the PSD-95 and subsequently forms a ternary complex with D₁DR through PSD-95. Calcyon is phosphorylated on Ser-169 by the PKC activator phorbol 12-myristate 13-acetate or by the D₁DR agonist SKF-81297, and its phosphorylation increases its association with PSD-95 and recruitment to the cell surface. Interestingly, the internalization of D₁DR at the cell surface was enhanced by phorbol 12-myristate 13-acetate and SKF-81297 in the presence of calcyon, but not in the presence of its S169A phospho-deficient mutant, suggesting that the phosphorylation of calcyon and the internalization of the surface D₁DR are tightly correlated. Our results suggest that calcyon regulates D₁DR trafficking by forming a ternary complex with D₁DR through PSD-95 and thus possibly linking glutamatergic and dopamine receptor signalings. This also raises the possibility that a novel ternary complex could represent a potential therapeutic target for the modulation of related neuropsychiatric disorders.