Altered G Protein Coupling in Olfactory Neuroepithelial Cells From Patients With Schizophrenia

• Published in: Schizophrenia bulletin Vol. 42; no. 2; pp. 377 - 385
• Main Authors: Borgmann-Winter, Karin E., Wang, Hoau-Yan, Ray, Rabindranath, Willis, Brooke R., Moberg, Paul J., Rawson, Nancy E., Gur, Raquel E., Turetsky, Bruce I., Hahn, Chang-Gyu
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.03.2016
• Subjects: Adult; Cells, Cultured; Female; GTP-Binding Protein alpha Subunits - metabolism; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; Humans; Male; Middle Aged; Nasal Septum - cytology; Neuroepithelial Cells - metabolism; Olfaction Disorders - etiology; Olfaction Disorders - metabolism; Regular; Schizophrenia - complications; Schizophrenia - metabolism; Signal Transduction - physiology; Turbinates - cytology; serotonin; olfactory; schizophrenia; dopamine; G protein
• ISSN: 0586-7614; 1745-1701; 1745-1701
• DOI: 10.1093/schbul/sbv129

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.