Calcyon Forms a Novel Ternary Complex with Dopamine D-1 Receptor through PSD-95 Protein and Plays a Role in Dopamine Receptor Internalization

Abstract

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.