title: A dopamine D2 receptor-DISC1 protein complex may contribute to antipsychotic-like effects.
abstract: Current antipsychotic drugs primarily target dopamine D2 receptors (D2Rs), in conjunction with other receptors such as those for serotonin. However, these drugs have serious side effects such as extrapyramidal symptoms (EPS) and diabetes. Identifying a specific D2R signaling pathway that could be targeted for antipsychotic effects, without inducing EPS, would be a significant improvement in the treatment of schizophrenia. We report here that the D2R forms a protein complex with Disrupted in Schizophrenia 1 (DISC1) that facilitates D2R-mediated glycogen synthase kinase (GSK)-3 signaling and inhibits agonist-induced D2R internalization. D2R-DISC1 complex levels are increased in conjunction with decreased GSK-3α/β (Ser21/9) phosphorylation in both postmortem brain tissue from schizophrenia patients and in Disc1-L100P mutant mice, an animal model with behavioral abnormalities related to schizophrenia. Administration of an interfering peptide that disrupts the D2R-DISC1 complex successfully reverses behaviors relevant to schizophrenia but does not induce catalepsy, a strong predictor of EPS in humans.
authors.affiliation: Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada.
authors.forename: Ping
authors.initials: P
authors.lastname: Su
authors.affiliation: Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada.
authors.forename: Shupeng
authors.initials: S
authors.lastname: Li
authors.affiliation: Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada.
authors.forename: Sheng
authors.initials: S
authors.lastname: Chen
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Lipina
authors.affiliation: Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada.
authors.forename: Terence K Y
authors.initials: TK
authors.lastname: Lai
authors.affiliation: Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada.
authors.forename: Frankie H F
authors.initials: FH
authors.lastname: Lee
authors.affiliation: Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada.
authors.forename: Hailong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada.
authors.forename: Dongxu
authors.initials: D
authors.lastname: Zhai
authors.affiliation: Department of Physiology & Pharmacology, University of Western Ontario, London, ON N6A 5 K8, Canada.
authors.forename: Stephen S G
authors.initials: SS
authors.lastname: Ferguson
authors.affiliation: Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada; Departments of Psychology, Toronto, ON M5S 2J7, Canada; Psychiatry, University of Toronto, Toronto, ON M5S 2J7, Canada.
authors.forename: José N
authors.initials: JN
authors.lastname: Nobrega
authors.affiliation: Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada; Psychiatry, University of Toronto, Toronto, ON M5S 2J7, Canada.
authors.forename: Albert H C
authors.initials: AH
authors.lastname: Wong
authors.affiliation: Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
authors.forename: John C
authors.initials: JC
authors.lastname: Roder
authors.affiliation: Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada; Departments of Psychology, Toronto, ON M5S 2J7, Canada; Psychiatry, University of Toronto, Toronto, ON M5S 2J7, Canada.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Fletcher
authors.affiliation: Department of Neuroscience, Centre for Addiction and Mental Health, Toronto, ON M5T 1R8, Canada; Psychiatry, University of Toronto, Toronto, ON M5S 2J7, Canada. Electronic address: f.liu.a@utoronto.ca.
authors.forename: Fang
authors.initials: F
authors.lastname: Liu
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D019390:Arrestins / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D002375:Catalepsy / Q000139:chemically induced; D002966:Clathrin / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation; D065808:Prepulse Inhibition / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism*; D012559:Schizophrenia / Q000378:metabolism*; D000071557:beta-Arrestins
chemical_list: D014150:Antipsychotic Agents; D019390:Arrestins; D002966:Clathrin; C412476:DISC1 protein, human; C498794:Disc1 protein, mouse; D009419:Nerve Tissue Proteins; D010455:Peptides; D017448:Receptors, Dopamine D2; D000071557:beta-Arrestins; D000661:Amphetamine; D038362:Glycogen Synthase Kinase 3