title: GSK-3β Interacts with Dopamine D1 Receptor to Regulate Receptor Function: Implication for Prefrontal Cortical D1 Receptor Dysfunction in Schizophrenia.
abstract: BACKGROUND
  Impaired dopamine D1 receptor (D1R) function in prefrontal cortex (PFC) is believed to contribute to the PFC hypofunction that has been hypothesized to be associated with negative symptoms and cognitive deficits in schizophrenia. It is therefore critical to understand the mechanisms for modulation of D1R function.
  
  
  OBJECTIVE
  To investigate the physical interaction and functional modulation between D1R and GSK-3β.
  
  
  RESULTS
  D1R and GSK-3β physically interact in cultured cells and native brain tissues. This direct interaction was found to occur at the S(417)PALS(421) motif in the C-terminus of D1R. Inhibition of GSK-3β impaired D1R activation along with a decrease in D1R-GSK-3β interaction. GSK-3β inhibition reduced agonist-stimulated D1R desensitization and endocytosis, the latter associated with the reduction of membrane translocation of β-arrestin-2. Similarly, inhibition of GSK-3β in rat PFC also resulted in impaired D1R activation and association with GSK-3β. Moreover, in a NMDA antagonist animal model of schizophrenia, we detected a decrease in prefrontal GSK-3β activity and D1R-GSK-3β association and decreased D1R activation in the PFC.
  
  
  CONCLUSIONS
  The present work identified GSK-3β as a new interacting protein for D1R functional regulation and revealed a novel mechanism for GSK-3β-regulated D1R function which may underlie D1R dysfunction in schizophrenia.
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Jing-Ru
authors.initials: JR
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Pei-Hua
authors.initials: PH
authors.lastname: Sun
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Soochow University, Suzhou, Jiangsu, China.
authors.forename: Zhao-Xiang
authors.initials: ZX
authors.lastname: Ren
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Northwestern Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Meltzer
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, Soochow University, Suzhou, Jiangsu, China.|College of Pharmaceutical Sciences and the Collaborative Innovation Center for Brain Science, Soochow University, Suzhou, China.
authors.forename: Xue-Chu
authors.initials: XC
authors.lastname: Zhen
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology; D004705:Endocytosis / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018818:Fenoldopam / Q000494:pharmacology; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D018021:Lithium Chloride / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D012559:Schizophrenia / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D000071557:beta-Arrestins / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D018491:Dopamine Agonists; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D017447:Receptors, Dopamine D1; C417521:SB 216763; D000071557:beta-Arrestins; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D000242:Cyclic AMP; D000071679:Glycogen Synthase Kinase 3 beta; D018021:Lithium Chloride; D018818:Fenoldopam
keywords: Desensitization; Dopamine D1 receptor; GSK-3β; Internalization; Schizophrenia; β-arrestin