Abstract

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

Links

Publisher Full Text

Authors

Gomes JR, Costa JT, Melo CV, Felizzi F, Monteiro P, Pinto MJ, Inácio AR, Wieloch T, Almeida RD, Grãos M, Duarte CB

Institution

CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.

Source

The Journal of neuroscience : the official journal of the Society for Neuroscience 32:13 2012 Mar 28 pg 4610-22

MeSH

Animals
Anisomycin
Brain-Derived Neurotrophic Factor
Calpain
Cell Death
Corpus Striatum
Embryo, Mammalian
Gene Expression Regulation
Glutamic Acid
Hippocampus
Isoenzymes
Kainic Acid
Neurons
Neuroprotective Agents
Primary Cell Culture
Rats
Rats, Wistar
Receptor, trkB
Signal Transduction
rhoA GTP-Binding Protein

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22457507