title: Increased G protein-coupled receptor kinase (GRK) expression in the anterior cingulate cortex in schizophrenia.
abstract: BACKGROUND
  Current pharmacological treatments for schizophrenia target G protein-coupled receptors (GPCRs), including dopamine receptors. Ligand-bound GPCRs are regulated by a family of G protein-coupled receptor kinases (GRKs), members of which uncouple the receptor from heterotrimeric G proteins, desensitize the receptor, and induce receptor internalization via the arrestin family of scaffolding and signaling molecules. GRKs initiate the activation of downstream signaling pathways, can regulate receptors and signaling molecules independent of GPCR phosphorylation, and modulate epigenetic regulators like histone deacetylases (HDACs). We hypothesize that the expression of GRK proteins is altered in schizophrenia, consistent with previous findings of alterations upstream and downstream from this family of molecules that facilitate intracellular signaling processes.
  
  
  METHODS
  In this study, we measured protein expression via Western blot analysis for GRKs 2, 3, 5, and 6 in the anterior cingulate cortex of patients with schizophrenia (n=36) and a comparison group (n=33). To control for antipsychotic treatment, we measured these same targets in haloperidol-treated vs. untreated rats (n=10 for both).
  
  
  RESULTS
  We found increased levels of GRK5 in schizophrenia. No changes were detected in GRK protein expression in rats treated with haloperidol decanoate for 9 months.
  
  
  CONCLUSIONS
  These data suggest that increased GRK5 expression may contribute to the pathophysiology of schizophrenia via abnormal regulation of the cytoskeleton, endocytosis, signaling, GPCRs, and histone modification.
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, CARE 5830, 231 Albert Sabin Way, Cincinnati, OH 45267-0583, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Funk
authors.affiliation: Department of Psychiatry, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1230, New York, NY 10029, USA.
authors.forename: Vahram
authors.initials: V
authors.lastname: Haroutunian
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama Birmingham, SC 560, 1530 3rd Avenue South, Birmingham, AL 35294, USA; Evelyn F. McKnight Brain Institute, University of Alabama Birmingham, Shelby 911, 1530 3rd Avenue South, Birmingham, AL 35294, USA.
authors.forename: James H
authors.initials: JH
authors.lastname: Meador-Woodruff
authors.affiliation: Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, CARE 5830, 231 Albert Sabin Way, Cincinnati, OH 45267-0583, USA. Electronic address: robert.mccullumsmith@uc.edu.
authors.forename: Robert E
authors.initials: RE
authors.lastname: McCullumsmith
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D005260:Female; D054768:G-Protein-Coupled Receptor Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006179:Gyrus Cinguli / Q000187:drug effects / Q000378:metabolism*; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D008297:Male; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley; D012559:Schizophrenia / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D014150:Antipsychotic Agents; D054768:G-Protein-Coupled Receptor Kinases; D006220:Haloperidol
keywords: G protein-coupled receptor (GPCR); G protein-coupled receptor kinase (GRK); Histone deacetylase (HDAC); Kinase; Postmortem; Schizophrenia