title: Calcyon forms a novel ternary complex with dopamine D1 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 (D(1)DR), is implicated in various neuropsychiatric disorders including schizophrenia, bipolar disorder, and attention deficit hyperactivity disorder. Although its direct interaction with D(1)DR has been shown to be misinterpreted, it still plays important roles in D(1)DR signaling. Here, we found that calcyon interacts with the PSD-95 and subsequently forms a ternary complex with D(1)DR through PSD-95. Calcyon is phosphorylated on Ser-169 by the PKC activator phorbol 12-myristate 13-acetate or by the D(1)DR agonist SKF-81297, and its phosphorylation increases its association with PSD-95 and recruitment to the cell surface. Interestingly, the internalization of D(1)DR 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 D(1)DR are tightly correlated. Our results suggest that calcyon regulates D(1)DR trafficking by forming a ternary complex with D(1)DR 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.
authors: Department of Physiology, Seoul National University College of Medicine, Seoul, Korea. gkckdaks@snu.ac.kr
authors: Chang Man
authors: CM
authors: Ha
authors: Daehun
authors: D
authors: Park
authors: Jeong-Kyu
authors: JK
authors: Han
authors: June-ill
authors: JI
authors: Jang
authors: Jae-Yong
authors: JY
authors: Park
authors: Eun Mi
authors: EM
authors: Hwang
authors: Heon
authors: H
authors: Seok
authors: Sunghoe
authors: S
authors: Chang
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D004705:Endocytosis; D015723:Gene Library; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry*; D008565:Membrane Proteins / Q000737:chemistry*; D008959:Models, Neurological; D009474:Neurons / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D051381:Rats; D011954:Receptors, Dopamine / Q000737:chemistry; D017447:Receptors, Dopamine D1 / Q000737:chemistry*; D015398:Signal Transduction
chemical_list: C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; C405464:calcyon