title: Altered G Protein Coupling in Olfactory Neuroepithelial Cells From Patients With Schizophrenia.
abstract: Increasing evidence suggests that olfactory dysfunction is an endophenotype of schizophrenia, and thus the olfactory system can be studied both in relation to this sensory dysfunction and also as a means of examining pathophysiologic mechanisms of schizophrenia. In this study, we examined human olfactory neuroepithelial (ON) biopsy tissues and their in vitro culture cells for ligand-induced guanine nucleotide-binding protein (G protein) activation and downstream signaling. We assessed the binding of a nonhydrolyzable GTP analogue [(35)S]GTPγS binding to specific G protein subtypes in response to odorants, dopamine, or serotonin in ON cell membranes from matched schizophrenia-control subjects. In response to odorant mixtures, we found decreased [(35)S]GTPγS binding to Gαs/olf in schizophrenia patients. These changes were not mediated by mRNA expression of key molecules of G protein coupling, including adenylate cyclase III (ACIII), protein kinase A (PKA), protein kinase Cγ (PKCγ), or Gαs or Gαolf in ON cells or ON biopsy tissues. In contrast, dopamine (DA)- and serotonin (5HT)-induced S(35)-GTPγS binding to Gαs/olf and Gαq/11 were significantly increased in schizophrenia cases, while these parameters were strikingly reduced by in vitro treatment with antipsychotics. Patients with schizophrenia exhibit increases in electrolfactogram (EOG) recordings, suggesting enhanced odorant-induced activation. Our results of decreased odorant-induced G protein activation may point further downstream for underlying mechanisms for increased EOG measures. Increased G protein activation in response to DA and 5HT may suggest increased postreceptor DA or 5HT signaling as an additional mechanism of dopaminergic or serotonergic dysregulation in schizophrenia.
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA; Department of Child and Adolescent Psychiatry and Behavioral Sciences, Children's Hospital of Philadelphia, Philadelphia, PA;
authors.forename: Karin E
authors.initials: KE
authors.lastname: Borgmann-Winter
authors.affiliation: Department of Physiology, Pharmacology and Neuroscience, City University of New York Medical School, New York, NY;
authors.forename: Hoau-Yan
authors.initials: HY
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA;
authors.forename: Rabindranath
authors.initials: R
authors.lastname: Ray
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA;
authors.forename: Brooke R
authors.initials: BR
authors.lastname: Willis
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA;
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Moberg
authors.affiliation: AFB International, 3 Research Park Drive, St. Charles, MO.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Rawson
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA;
authors.forename: Raquel E
authors.initials: RE
authors.lastname: Gur
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA;
authors.forename: Bruce I
authors.initials: BI
authors.lastname: Turetsky
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA; hahnc@mail.med.upenn.edu.
authors.forename: Chang-Gyu
authors.initials: CG
authors.lastname: Hahn
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009300:Nasal Septum / Q000166:cytology; D046569:Neuroepithelial Cells / Q000378:metabolism*; D000857:Olfaction Disorders / Q000209:etiology / Q000378:metabolism*; D012559:Schizophrenia / Q000150:complications / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014420:Turbinates / Q000166:cytology
chemical_list: D044385:GTP-Binding Protein alpha Subunits; C084618:olfactory G protein subunit alpha olf; D016244:Guanosine 5'-O-(3-Thiotriphosphate)
keywords: G protein; dopamine; olfactory; schizophrenia; serotonin