科研之友
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摘要
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 [S-35]GTP gamma S binding to specific G protein subtypes in response to odorants, dopamine, or serotonin in ON cell membranes from matched schizophreniacontrol subjects. In response to odorant mixtures, we found decreased [S-35]GTP gamma S binding to G alpha s/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 C gamma (PKC gamma), or G alpha s or G alpha olf in ON cells or ON biopsy tissues. In contrast, dopamine (DA)- and serotonin (5HT)- induced S-35-GTP gamma S binding to G alpha s/olf and G alpha q/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.
- 出版日期2016-3
