Full length TrkB potentiates estrogen receptor alpha mediated transcription suggesting convergence of susceptibility pathways in schizophrenia

In this study, we determined if estrogen receptor alpha (ER alpha) 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 ER alpha-mediated transcription. This synergistic effect of TrkB-TK+ on ER alpha-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 ER alpha, leading to an induction in ER alpha-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 ER alpha-mediated transcription at EREs. Considering that both ER alpha 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 ER alpha, and that transcriptional regulation by ER alpha may be decreased by reductions in TrkB-TK+. (C) 2010 Elsevier Inc. All rights reserved.