PMID- 15145081
OWN - NLM
STAT- MEDLINE
DCOM- 20040729
LR  - 20131121
IS  - 0306-4522 (Print)
IS  - 0306-4522 (Linking)
VI  - 126
IP  - 1
DP  - 2004
TI  - Ethanol inhibits brain-derived neurotrophic factor-mediated intracellular 
      signaling and activator protein-1 activation in cerebellar granule neurons.
PG  - 149-62
AB  - Developmental exposure to ethanol causes profound damage to the cerebellum, 
      ranging from aberration in neuronal differentiation to cell loss. As a major 
      neurotrophic factor, brain-derived neurotrophic factor (BDNF) and its receptor 
      TrkB are expressed in the developing, as well as adult, cerebellum. Many 
      neurotrophic effects of BDNF are mediated by gene transcription. We hypothesized 
      that ethanol interfered with BDNF signaling and disrupted BDNF-regulated 
      transcriptional activity. Using a transgenic mouse model expressing an activator 
      protein-1 (AP-1) luciferase reporter construct, we demonstrated that BDNF 
      stimulated AP-1 transactivation in cultured cerebellar granule neurons. This 
      observation was validated by the study using a human neuronal cell line 
      expressing inducible TrkB (TB8 neuroblastoma cells). BDNF induced AP-1 
      transactivation, as well as increased the binding activity of AP-1 protein 
      complex to a DNA sequence containing AP-1 sites in TB8 cells. BDNF-mediated AP-1 
      activation was mediated by PI3K/Akt and JNK pathways; BDNF activated Akt and 
      JNKs, and blocking these pathways significantly inhibited BDNF-stimulated AP-1 
      transactivation. More importantly, ethanol inhibited BDNF-mediated activation of 
      PI3K/Akt and JNKs, and blocked BDNF-stimulated AP-1 activation. Since ethanol did 
      not affect either the expression or autophosphorylation of TrkB, it could be 
      concluded that the site of ethanol action was downstream of TrkB. The present 
      study establishes that this AP-1 reporter transgenic mouse model is valuable for 
      assessing AP-1 activity in the CNS neurons. Our results provide an insight into 
      molecular mechanism(s) of ethanol action.
FAU - Li, Z
AU  - Li Z
AD  - Department of Microbiology, West Virginia University School of Medicine, Robert 
      C. Byrd Health Sciences Center, Morgantown, WV 26506, USA.
FAU - Ding, M
AU  - Ding M
FAU - Thiele, C J
AU  - Thiele CJ
FAU - Luo, J
AU  - Luo J
LA  - eng
GR  - AA12968/AA/NIAAA NIH HHS/United States
GR  - CA90385/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Neuroscience
JT  - Neuroscience
JID - 7605074
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Central Nervous System Depressants)
RN  - 0 (Transcription Factor AP-1)
RN  - 3K9958V90M (Ethanol)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.10.1 (Receptor, trkB)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/*pharmacology
MH  - Cell Communication/drug effects
MH  - Cell Line, Tumor
MH  - Central Nervous System Depressants/*pharmacology
MH  - Cerebellum/*cytology
MH  - Drug Interactions
MH  - Ethanol/*pharmacology
MH  - Humans
MH  - JNK Mitogen-Activated Protein Kinases
MH  - Mice
MH  - Mice, Transgenic
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - Neuroblastoma
MH  - Neurons/cytology/*drug effects/metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Phosphorylation/drug effects
MH  - Receptor, trkB/metabolism
MH  - Transcription Factor AP-1/*metabolism
EDAT- 2004/05/18 05:00
MHDA- 2004/07/30 05:00
CRDT- 2004/05/18 05:00
PHST- 2004/03/18 00:00 [accepted]
PHST- 2004/05/18 05:00 [pubmed]
PHST- 2004/07/30 05:00 [medline]
PHST- 2004/05/18 05:00 [entrez]
AID - S0306452204002234 [pii]
AID - 10.1016/j.neuroscience.2004.03.028 [doi]
PST - ppublish
SO  - Neuroscience. 2004;126(1):149-62. doi: 10.1016/j.neuroscience.2004.03.028.