Robust stimulation of TrkB induces delayed increases in BDNF and Arc mRNA expressions in cultured rat cortical neurons via distinct mechanisms.
In cultures of rat cortical neurons, we found that stimulation of tyrosine receptor kinase B (TrkB) with brain-derived neurotrophic factor (BDNF) induced a biphasic expression of BDNF exon IV-IX mRNA, which became obvious 1-3 h (primary induction) and 24-72 h (delayed induction) after the stimulation, and characterized the delayed induction in relation to the mRNA expression of activity-regulated cytoskeleton-associated protein (Arc). Withdrawal of BDNF from the medium after stimulation for 3 h allowed the delayed induction, which was caused at the transcriptional level and dependent upon the initial contact between exogenously added BDNF and TrkB, the effect of which was time- and dose-dependent. The primary induction was controlled by the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) whereas the secondary induction by the calcium (Ca(2+)) signaling pathway. The enhanced Arc or Zif268 mRNA expression was controlled by activation of the ERK/MAPK pathway, both of which were repressed by blocking the binding of endogenously synthesized BDNF to TrkB. Thus, robust stimulation of TrkB autonomously induces delayed BDNF mRNA expression in an activity-dependent manner in rat cortical neurons, resulting in the stimulation of Arc mRNA expression through endogenously synthesized BDNF, the process being orchestrated by the Ca(2+) and ERK/MAPK signaling pathways.
Yasuda
Makoto
M
Department of Biological Chemistry, Faculty of Pharmaceutical Sciences, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama, Japan.
Fukuchi
Mamoru
M
Tabuchi
Akiko
A
Kawahara
Masahiro
M
Tsuneki
Hiroshi
H
Azuma
Yuko
Y
Chiba
Yusuke
Y
Tsuda
Masaaki
M
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis*; D002478:Cells, Cultured; D016895:Culture Media, Serum-Free; D003598:Cytoskeletal Proteins / Q000096:biosynthesis*; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D017781:Genes, Immediate-Early / Q000187:drug effects; D015151:Immunoblotting; D007202:Indicators and Reagents; D008156:Luciferases / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000819:agonists*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection
D019208:Brain-Derived Neurotrophic Factor; D016895:Culture Media, Serum-Free; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; D007202:Indicators and Reagents; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C092069:activity regulated cytoskeletal-associated protein; D008156:Luciferases; D020813:Receptor, trkB; D048049:Extracellular Signal-Regulated MAP Kinases