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

Rodrigues Gomes, Joao Carlos; Costa, João T; Melo, Carlos V; Felizzi, Federico; Monteiro, Patrícia; Pinto, Maria J; Inacio, Ana LU ; Wieloch, Tadeusz LU ; Almeida, Ramiro D and Grãos, Mário, et al. (2012) In The Journal of neuroscience : the official journal of the Society for Neuroscience 32(13). p.4610-4622
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.... (More)
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. (Less)
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published
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in
The Journal of neuroscience : the official journal of the Society for Neuroscience
volume
32
issue
13
pages
4610 - 4622
publisher
Society for Neuroscience
external identifiers
  • WOS:000302159400024
  • PMID:22457507
  • Scopus:84859013000
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.0374-12.2012
language
English
LU publication?
yes
id
26d6ca70-d6ca-4398-85a5-4a43f46c3cd1 (old id 2431367)
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http://www.ncbi.nlm.nih.gov/pubmed/22457507?dopt=Abstract
date added to LUP
2012-04-03 14:17:57
date last changed
2016-10-31 07:44:33
@misc{26d6ca70-d6ca-4398-85a5-4a43f46c3cd1,
  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.},
  author       = {Rodrigues Gomes, Joao Carlos and Costa, João T and Melo, Carlos V and Felizzi, Federico and Monteiro, Patrícia and Pinto, Maria J and Inacio, Ana and Wieloch, Tadeusz and Almeida, Ramiro D and Grãos, Mário and Duarte, Carlos B},
  issn         = {1529-2401},
  language     = {eng},
  number       = {13},
  pages        = {4610--4622},
  publisher    = {ARRAY(0x87f6a88)},
  series       = {The Journal of neuroscience : the official journal of the Society for Neuroscience},
  title        = {Excitotoxicity Downregulates TrkB.FL Signaling and Upregulates the Neuroprotective Truncated TrkB Receptors in Cultured Hippocampal and Striatal Neurons.},
  url          = {http://dx.doi.org/10.1523/JNEUROSCI.0374-12.2012},
  volume       = {32},
  year         = {2012},
}