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A Dopamine D2 Receptor-DISC1 Protein Complex may Contribute to Antipsychotic-Like Effects

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 ta... Full description

Journal Title: Neuron 2014-12-17, Vol.84 (6), p.1302-1316
Main Author: Su, Ping
Other Authors: Li, Shupeng , Chen, Sheng , Lipina, Tatiana V , Wang, Min , Lai, Terence K.Y , Lee, Frankie H.F , Zhang, Hailong , Zhai, Dongxu , Ferguson, Stephen S.G , Nobrega, José N , Wong, Albert H.C , Roder, John C , Fletcher, Paul J , Liu, Fang
Format: Electronic Article Electronic Article
Language: English
Subjects:
Quelle: Alma/SFX Local Collection
Publisher: United States: Elsevier Inc
ID: ISSN: 0896-6273
Link: https://www.ncbi.nlm.nih.gov/pubmed/25433637
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title: A Dopamine D2 Receptor-DISC1 Protein Complex may Contribute to Antipsychotic-Like Effects
format: Article
creator:
  • Su, Ping
  • Li, Shupeng
  • Chen, Sheng
  • Lipina, Tatiana V
  • Wang, Min
  • Lai, Terence K.Y
  • Lee, Frankie H.F
  • Zhang, Hailong
  • Zhai, Dongxu
  • Ferguson, Stephen S.G
  • Nobrega, José N
  • Wong, Albert H.C
  • Roder, John C
  • Fletcher, Paul J
  • Liu, Fang
subjects:
  • Amphetamine - pharmacology
  • Analysis
  • Animal behavior
  • Animals
  • Antipsychotic Agents - pharmacology
  • Antipsychotic drugs
  • Arrestins - metabolism
  • beta-Arrestins
  • Brain - metabolism
  • Catalepsy - chemically induced
  • Clathrin - metabolism
  • Dopamine
  • Glucose metabolism
  • Glycogen
  • Glycogen Synthase Kinase 3 - metabolism
  • Humans
  • Kinases
  • Male
  • Medical research
  • Mice
  • Motor Activity - drug effects
  • Mutation
  • Nerve Tissue Proteins - genetics
  • Nerve Tissue Proteins - metabolism
  • Neuroscience(all)
  • Neurosciences
  • Peptides
  • Peptides - pharmacology
  • Phenols
  • Phosphorylation
  • Physiological aspects
  • Prepulse Inhibition - drug effects
  • Protein Binding - drug effects
  • Psychotropic drugs
  • Rats
  • Receptors, Dopamine D2 - agonists
  • Receptors, Dopamine D2 - metabolism
  • Rodents
  • Schizophrenia
  • Schizophrenia - metabolism
  • Synthesis
ispartof: Neuron, 2014-12-17, Vol.84 (6), p.1302-1316
description: 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. [Display omitted] •D2R-DISC1 complex is increased in postmortem brain from schizophrenia patients•GSK-3α/β phosphorylation is also decreased in postmortem brain of these patients•Activation of D2R enhances D2R-DISC1 coupling and reduces GSK-3α/β phosphorylation•Disrupting the D2R-DISC1 complex has antipsychotic-like effects without EPS in vivo DISC1 is a prominent schizophrenia susceptibility gene, and the main target of antipsychotic medications is the dopamine D2 receptor. Su et al. show that DISC1 and D2 form a complex. Disruption of this complex has antipsychotic-like effects without neurological side effects.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0896-6273
fulltext: fulltext
issn:
  • 0896-6273
  • 1097-4199
url: Link


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descriptionCurrent 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. [Display omitted] •D2R-DISC1 complex is increased in postmortem brain from schizophrenia patients•GSK-3α/β phosphorylation is also decreased in postmortem brain of these patients•Activation of D2R enhances D2R-DISC1 coupling and reduces GSK-3α/β phosphorylation•Disrupting the D2R-DISC1 complex has antipsychotic-like effects without EPS in vivo DISC1 is a prominent schizophrenia susceptibility gene, and the main target of antipsychotic medications is the dopamine D2 receptor. Su et al. show that DISC1 and D2 form a complex. Disruption of this complex has antipsychotic-like effects without neurological side effects.
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subjectAmphetamine - pharmacology ; Analysis ; Animal behavior ; Animals ; Antipsychotic Agents - pharmacology ; Antipsychotic drugs ; Arrestins - metabolism ; beta-Arrestins ; Brain - metabolism ; Catalepsy - chemically induced ; Clathrin - metabolism ; Dopamine ; Glucose metabolism ; Glycogen ; Glycogen Synthase Kinase 3 - metabolism ; Humans ; Kinases ; Male ; Medical research ; Mice ; Motor Activity - drug effects ; Mutation ; Nerve Tissue Proteins - genetics ; Nerve Tissue Proteins - metabolism ; Neuroscience(all) ; Neurosciences ; Peptides ; Peptides - pharmacology ; Phenols ; Phosphorylation ; Physiological aspects ; Prepulse Inhibition - drug effects ; Protein Binding - drug effects ; Psychotropic drugs ; Rats ; Receptors, Dopamine D2 - agonists ; Receptors, Dopamine D2 - metabolism ; Rodents ; Schizophrenia ; Schizophrenia - metabolism ; Synthesis
ispartofNeuron, 2014-12-17, Vol.84 (6), p.1302-1316
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descriptionCurrent 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. [Display omitted] •D2R-DISC1 complex is increased in postmortem brain from schizophrenia patients•GSK-3α/β phosphorylation is also decreased in postmortem brain of these patients•Activation of D2R enhances D2R-DISC1 coupling and reduces GSK-3α/β phosphorylation•Disrupting the D2R-DISC1 complex has antipsychotic-like effects without EPS in vivo DISC1 is a prominent schizophrenia susceptibility gene, and the main target of antipsychotic medications is the dopamine D2 receptor. Su et al. show that DISC1 and D2 form a complex. Disruption of this complex has antipsychotic-like effects without neurological side effects.
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35Receptors, Dopamine D2 - agonists
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titleA Dopamine D2 Receptor-DISC1 Protein Complex may Contribute to Antipsychotic-Like Effects
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abstractCurrent 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. [Display omitted] •D2R-DISC1 complex is increased in postmortem brain from schizophrenia patients•GSK-3α/β phosphorylation is also decreased in postmortem brain of these patients•Activation of D2R enhances D2R-DISC1 coupling and reduces GSK-3α/β phosphorylation•Disrupting the D2R-DISC1 complex has antipsychotic-like effects without EPS in vivo DISC1 is a prominent schizophrenia susceptibility gene, and the main target of antipsychotic medications is the dopamine D2 receptor. Su et al. show that DISC1 and D2 form a complex. Disruption of this complex has antipsychotic-like effects without neurological side effects.
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pmid25433637
doi10.1016/j.neuron.2014.11.007
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