title: Full length TrkB potentiates estrogen receptor alpha mediated transcription suggesting convergence of susceptibility pathways in schizophrenia.
abstract: In this study, we determined if estrogen receptor alpha (ERα) can interact with the full length tropomyosin receptor kinase B (TrkB-TK+), both of which are implicated in schizophrenia pathogenesis. Using neuronal (SHSY5Y) and non-neuronal (CHOK1) cell-lines, we showed that TrkB-TK+ can increase transcription at estrogen response elements (EREs) with and without exogenous estrogen treatment. In the presence of estrogen, TrkB-TK+ further potentiated the effect of estrogen stimulation on ERα-mediated transcription. This synergistic effect of TrkB-TK+ on ERα-mediated transcription was not due to direct effects of TrkB-TK+ in the nucleus, but occurred through cytoplasmic signaling of TrkB-TK+ via the MAPK/ERK pathway to phosphorylate ERα, leading to an induction in ERα-mediated transcription. When we examined the PI3K/AKT pathway, we found that PI3K/AKT activity constitutively inhibited baseline transcription at EREs. Furthermore, we showed that signaling via PI3K/AKT inhibited TrkB-TK+-dependent transcriptional potentiation at EREs. Our findings suggest that TrkB-TK+-linked second messenger signaling pathways can reciprocally regulate ERα-mediated transcription at EREs. Considering that both ERα and TrkB-TK+ expression are reduced in schizophrenia, our findings suggest that dysfunction in TrkB-TK+ signaling may occur upstream of, or in conjunction with a dysfunction in ERα, and that transcriptional regulation by ERα may be decreased by reductions in TrkB-TK+.
authors.affiliation: Schizophrenia Research Institute, Sydney, Australia.
authors.forename: Jenny
authors.initials: J
authors.lastname: Wong
authors.forename: Heng Giap
authors.initials: HG
authors.lastname: Woon
authors.forename: Cynthia Shannon
authors.initials: CS
authors.lastname: Weickert
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002460:Cell Line; D002867:Chromones / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D006801:Humans; D009025:Morpholines / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000187:drug effects; D012559:Schizophrenia / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002867:Chromones; D004958:Estradiol; D047628:Estrogen Receptor alpha; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020813:Receptor, trkB; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one