BDNF-mediated signal transduction is modulated by GSK3β and mood stabilizing agents

Lian Mai, Richard S. Jope, Xiaohua Li

Research output: Contribution to journalArticlepeer-review

156 Scopus citations

Abstract

Brain-derived neurotrophic factor (BDNF) is a major neurotrophin in the brain and abnormal regulation of BDNF may contribute to the pathophysiology of mood disorders. In the present study, we examined if alterations in the activity of glycogen synthase kinase-3-beta (GSK3β) or treatment with mood stabilizers modulated BDNF-mediated signal transduction pathways in differentiated human neuroblastoma SH-SY5Y cells. BDNF increased the phosphorylation of the forkhead transcription factor FKHRL1 through activation of the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway, and the phosphorylation of the cyclic AMP response element binding protein (CREB) through activation of extracellular signal-regulated kinase1/2 (ERK1/2). BDNF also increased serine9-phosphorylation of GSK3β, which inhibits GSK3Pβ activity. Overexpression of GSK3β did not affect BDNF-induced phosphorylation of Akt, ERK1/2, or FKHRL1, but abolished CREB phosphorylation induced by BDNF. This inhibition of BDNF-induced CREB phosphorylation in GSK3β-overexpressing SH-SY5Y cells was blocked by treatment with lithium. In contrast to lithium, sodium valproate and lamotrigine did not affect BDNF-mediated signaling, whereas carbamazepine induced a rapid and prolonged phosphorylation of ERK1/2 and CREB in the absence or the presence of BDNF. Therefore, increased GSK3β selectively attenuates BDNF-induced CREB phosphorylation, and lithium and carbamazepine can facilitate activation of CREB.

Original languageEnglish (US)
Pages (from-to)75-83
Number of pages9
JournalJournal of neurochemistry
Volume82
Issue number1
DOIs
StatePublished - 2002
Externally publishedYes

Keywords

  • Brain-derived neurotrophic factor
  • Cyclic AMP response element binding protein
  • Forkhead L1 transcription factor
  • Glycogen synthase kinase-3-beta
  • Lithium

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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