PMID- 16569708
OWN - NLM
STAT- MEDLINE
DCOM- 20061024
LR  - 20181201
IS  - 0026-895X (Print)
IS  - 0026-895X (Linking)
VI  - 70
IP  - 1
DP  - 2006 Jul
TI  - The phenotypic differentiation of locus ceruleus noradrenergic neurons mediated 
      by brain-derived neurotrophic factor is enhanced by corticotropin releasing 
      factor through the activation of a cAMP-dependent signaling pathway.
PG  - 30-40
AB  - We have developed a model system of locus ceruleus (LC) neurons in culture, in 
      which brain-derived neurotrophic factor (BDNF) induces the emergence of 
      noradrenergic neurons attested by the presence of tyrosine hydroxylase (TH) and 
      dopamine-beta-hydroxylase and the absence of phenylethanolamine 
      N-methyl-transferase. Although inactive in itself, the neuropeptide corticotropin 
      releasing factor (CRF) strongly amplified the effect of BDNF, increasing the 
      number of cells expressing TH and the active accumulation of noradrenaline by a 
      factor of 2 to 3 via a mechanism that was nonmitogenic. CRF also acted 
      cooperatively with neurotrophin-4, which like BDNF is a selective ligand of the 
      TrkB tyrosine kinase receptor. The effect of CRF but not that of BDNF was 
      prevented by astressin, a nonselective CRF-1/CRF-2 receptor antagonist. However, 
      only CRF-1 receptor transcripts were detectable in LC cultures, suggesting that 
      this receptor subtype mediated the effect of CRF. Consistent with the positive 
      coupling of CRF-1 receptors to adenylate cyclase, the trophic action of CRF was 
      mimicked by cAMP elevating agents. Epac, a guanine nucleotide exchange factor 
      directly activated by cAMP, contributed to the effect of CRF through the 
      stimulation of extracellular signal-regulated kinases (ERKs) 1/2. However, 
      downstream of ERK1/2 activation by CRF, the phenotypic induction of noradrenergic 
      neurons relied upon the stimulation of the phosphatidylinositol-3-kinase/Akt 
      transduction pathway by BDNF. Together, our results suggest that CRF participates 
      to the phenotypic differentiation of LC noradrenergic neurons during development. 
      Whether similar mechanisms account for the high degree of plasticity of these 
      neurons in the adult brain remains to be established.
FAU - Traver, Sabine
AU  - Traver S
AD  - Unite Mixte de Recherche 679, INSERM-UPMC Batiment Pharmacie, Hopital de la 
      Salpetriere, 47 bd de l'Hopital, 75013, Paris, France.
FAU - Marien, Marc
AU  - Marien M
FAU - Martin, Elodie
AU  - Martin E
FAU - Hirsch, Etienne C
AU  - Hirsch EC
FAU - Michel, Patrick P
AU  - Michel PP
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20060328
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Norepinephrine Plasma Membrane Transport Proteins)
RN  - 0 (Receptors, Corticotropin-Releasing Hormone)
RN  - 5CLY6W2H1M (CRF receptor type 1)
RN  - 9015-71-8 (Corticotropin-Releasing Hormone)
RN  - E0399OZS9N (Cyclic AMP)
RN  - EC 1.14.16.2 (Tyrosine 3-Monooxygenase)
RN  - EC 2.7.10.1 (Receptor, trkB)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3)
RN  - X4W3ENH1CV (Norepinephrine)
SB  - IM
MH  - Animals
MH  - Blotting, Western
MH  - Brain-Derived Neurotrophic Factor/*pharmacology
MH  - Cell Differentiation/*drug effects
MH  - Cells, Cultured
MH  - Corticotropin-Releasing Hormone/*pharmacology
MH  - Cyclic AMP/*metabolism
MH  - Dose-Response Relationship, Drug
MH  - Drug Synergism
MH  - Enzyme Activation/drug effects
MH  - Gene Expression/drug effects
MH  - Locus Coeruleus/cytology/drug effects/metabolism
MH  - Mitogen-Activated Protein Kinase 1/metabolism
MH  - Mitogen-Activated Protein Kinase 3/metabolism
MH  - Neurons/cytology/*drug effects/metabolism
MH  - Norepinephrine/metabolism
MH  - Norepinephrine Plasma Membrane Transport Proteins/genetics/metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Receptor, trkB/genetics/metabolism
MH  - Receptors, Corticotropin-Releasing Hormone/genetics/metabolism
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction/*drug effects
MH  - Tyrosine 3-Monooxygenase/genetics/metabolism
EDAT- 2006/03/30 09:00
MHDA- 2006/10/25 09:00
CRDT- 2006/03/30 09:00
PHST- 2006/03/30 09:00 [pubmed]
PHST- 2006/10/25 09:00 [medline]
PHST- 2006/03/30 09:00 [entrez]
AID - mol.106.022715 [pii]
AID - 10.1124/mol.106.022715 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2006 Jul;70(1):30-40. doi: 10.1124/mol.106.022715. Epub 2006 Mar 
      28.