PMID- 22457507
OWN - NLM
STAT- MEDLINE
DCOM- 20120518
LR  - 20211021
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 32
IP  - 13
DP  - 2012 Mar 28
TI  - Excitotoxicity downregulates TrkB.FL signaling and upregulates the 
      neuroprotective truncated TrkB receptors in cultured hippocampal and striatal 
      neurons.
PG  - 4610-22
LID - 10.1523/JNEUROSCI.0374-12.2012 [doi]
AB  - 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 PLCgamma 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.
FAU - Gomes, Joao R
AU  - Gomes JR
AD  - CNC-Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 
      Coimbra, Portugal.
FAU - Costa, Joao T
AU  - Costa JT
FAU - Melo, Carlos V
AU  - Melo CV
FAU - Felizzi, Federico
AU  - Felizzi F
FAU - Monteiro, Patricia
AU  - Monteiro P
FAU - Pinto, Maria J
AU  - Pinto MJ
FAU - Inacio, Ana R
AU  - Inacio AR
FAU - Wieloch, Tadeusz
AU  - Wieloch T
FAU - Almeida, Ramiro D
AU  - Almeida RD
FAU - Graos, Mario
AU  - Graos M
FAU - Duarte, Carlos B
AU  - Duarte CB
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Isoenzymes)
RN  - 0 (Neuroprotective Agents)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - 6C74YM2NGI (Anisomycin)
RN  - EC 2.7.10.1 (Receptor, trkB)
RN  - EC 3.4.22.- (Calpain)
RN  - EC 3.6.5.2 (rhoA GTP-Binding Protein)
RN  - SIV03811UC (Kainic Acid)
SB  - IM
MH  - Animals
MH  - Anisomycin/pharmacology
MH  - Brain-Derived Neurotrophic Factor/physiology
MH  - Calpain/antagonists & inhibitors/physiology
MH  - Cell Death/*drug effects/genetics
MH  - Corpus Striatum/drug effects/*metabolism
MH  - Embryo, Mammalian
MH  - Gene Expression Regulation/*drug effects
MH  - Glutamic Acid/toxicity
MH  - Hippocampus/drug effects/*metabolism
MH  - Isoenzymes/metabolism
MH  - Kainic Acid/*toxicity
MH  - Neurons/metabolism
MH  - Neuroprotective Agents/metabolism
MH  - Primary Cell Culture
MH  - Rats
MH  - Rats, Wistar
MH  - Receptor, trkB/*metabolism
MH  - Signal Transduction/drug effects/physiology
MH  - rhoA GTP-Binding Protein/antagonists & inhibitors/physiology
PMC - PMC6622054
EDAT- 2012/03/30 06:00
MHDA- 2012/05/19 06:00
PMCR- 2012/09/28
CRDT- 2012/03/30 06:00
PHST- 2012/03/30 06:00 [entrez]
PHST- 2012/03/30 06:00 [pubmed]
PHST- 2012/05/19 06:00 [medline]
PHST- 2012/09/28 00:00 [pmc-release]
AID - 32/13/4610 [pii]
AID - 3766152 [pii]
AID - 10.1523/JNEUROSCI.0374-12.2012 [doi]
PST - ppublish
SO  - J Neurosci. 2012 Mar 28;32(13):4610-22. doi: 10.1523/JNEUROSCI.0374-12.2012.