A Dopamine D2 Receptor-DISC1 Protein Complex may Contribute to Antipsychotic-Like Effects
| Autor: | Min Wang, Albert H.C. Wong, Stephen S. G. Ferguson, John C. Roder, Shupeng Li, Ping Su, Tatiana V. Lipina, Paul J. Fletcher, Hailong Zhang, Sheng Chen, Terence K. Y. Lai, José N. Nobrega, Dongxu Zhai, Fang Liu, Frankie H. F. Lee |
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| Rok vydání: | 2014 |
| Předmět: |
Male
medicine.medical_specialty Arrestins medicine.medical_treatment Neuroscience(all) Nerve Tissue Proteins Pharmacology Motor Activity DISC1 Glycogen Synthase Kinase 3 Mice Extrapyramidal symptoms GSK-3 Internal medicine Dopamine receptor D2 medicine Animals Humans Phosphorylation Antipsychotic Receptor beta-Arrestins Catalepsy biology Prepulse Inhibition Receptors Dopamine D2 General Neuroscience Brain medicine.disease Clathrin 3. Good health Rats Amphetamine Endocrinology Schizophrenia Mutation biology.protein medicine.symptom Signal transduction Psychology Peptides Antipsychotic Agents Protein Binding |
| Zdroj: | Neuron. 84(6):1302-1316 |
| ISSN: | 0896-6273 |
| DOI: | 10.1016/j.neuron.2014.11.007 |
| Popis: | Summary 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. Video Abstract |
| Databáze: | OpenAIRE |
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