Excitotoxicity Downregulates TrkB.FL Signaling and Upregulates the Neuroprotective Truncated TrkB Receptors in Cultured Hippocampal and Striatal Neurons

• DOI: 10.1523/jneurosci.0374-12.2012
• Publication Date: 2012-03-28T16:39:04Z
• Authors: João R. Gomes; João T. Costa; Carlos V. Melo; Federico Felizzi; Patrícia Monteiro; Maria J. Pinto; Ana R. Inácio; Tadeusz Wieloch; Ramiro D. Almeida; Mário Grãos; Carlos B. Duarte
• Keywords: Excitotoxicity

Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal survival through activation of TrkB receptors. The trkB gene encodes a full-length receptor tyrosine kinase (TrkB.FL) and its truncated (T1/T2) isoforms. We investigated the changes protein levels signaling activity under excitotoxic conditions, which are characteristic brain ischemia, traumatic injury, neurodegenerative disorders. Excitotoxic stimulation cultured rat hippocampal or striatal neurons downregulated TrkB.FL upregulated form (TrkB.T). Downregulation was mediated by calpains, whereas increase TrkB.T required transcription translation activities. receptors correlated with decrease BDNF-induced Ras/ERK PLCγ pathways. However, calpain inhibition, prevents degradation, did not preclude these On other hand, incubation anisomycin, to prevent upregulation TrkB.T, protected large extent activity, suggesting that may act as dominant-negatives. conditions inhibition RhoA, mediator death. BDNF fully transduced when present during glutamate, contrast partial protection observed cells overexpressing expressing GFP. These results indicate protects two distinct mechanisms: effects coupled signaling.