title: Fluvoxamine and sigma-1 receptor agonists dehydroepiandrosterone (DHEA)-sulfate induces the Ser473-phosphorylation of Akt-1 in PC12 cells.
abstract: OBJECTIVE
  The expression of brain-derived neurotrophic factor (BDNF) may be a downstream target of a variety of antidepressant treatments, and selective serotonin reuptake inhibitors (SSRIs) are used clinically for the treatment of depression. BDNF binds to and activates tyrosine kinases receptor (TrkB) to exert its effects. TrkB, after activation by ligands, stimulates phosphoinositide 3-kinase (PI3K). The downstream target of PI3K is Akt-1, a serine-threonine kinase. BDNF has signaling through the PLC-IP(3)/Ca(2+) pathway. Furthermore, the PLC-gamma/IP(3)/Ca(2+) pathway is regulated by the sigma-1 receptors. Here, we examined whether fluvoxamine (FLV) activated Akt-1 and increased phosphorylation of Akt-1 via sigma-1 receptor in PC12 cells.
  
  
  METHODS
  We examined the effect of the SSRI, FLV and BDNF on the phosphorylation levels of serine-threonine kinase Akt-1 in PC12 cells using immunoblotting techniques.
  
  
  RESULTS
  Treatment with 10 microM and 100 microM FLV of PC12 cells stimulated a 2.4- and 3.8-fold maximal increase in Ser(473)-phosphorylated Akt-1 levels at 40 min, respectively. Treatment with 50 ng/ml BDNF also stimulated Ser(473) -phosphorylated Akt-1 by 2.6-fold with a maximal increase at 5 min. In addition, the phosphorylation induced by FLV and BDNF was blocked by LY294002, a selective inhibitor of PI3K. The sigma-1 receptor agonists dehydroepiandrosterone (DHEA)-sulfate also stimulated a 2.1-fold increase in the level of Ser473-phosphorylated Akt-1.
  
  
  CONCLUSIONS
  This study demonstrates that fluvoxamine treatment rapidly increased phosphorylation of Akt-1. And BDNF activated Akt-1 phosphorylation by the TrkB/PI3K/Akt-1 pathway. We conclude that the phosphorylation of Akt-1, downstream of PI3K, was the key to their antidepressant effects.
authors.affiliation: Department of Neuropsychiatry, St. Marianna University School of Medicine, 2-16-1 Sugao Miyamae-ku Kawasaki, Kanagawa 216-8511, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Nakano
authors.forename: Kenichi
authors.initials: K
authors.lastname: Osada
authors.forename: Atsushi
authors.initials: A
authors.lastname: Misonoo
authors.forename: Keisuke
authors.initials: K
authors.lastname: Fujiwara
authors.forename: Miho
authors.initials: M
authors.lastname: Takahashi
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Ogawa
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Haga
authors.forename: Shigeto
authors.initials: S
authors.lastname: Kanai
authors.forename: Daisuke
authors.initials: D
authors.lastname: Tanaka
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Sasuga
authors.forename: Takuyoh
authors.initials: T
authors.lastname: Yanagida
authors.forename: Mikio
authors.initials: M
authors.lastname: Asakura
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamaguchi
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D016666:Fluvoxamine / Q000494:pharmacology*; D006801:Humans; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017480:Receptors, sigma / Q000819:agonists* / Q000378:metabolism; D012694:Serine / Q000378:metabolism*; D000097605:Sigma-1 Receptor
chemical_list: D019314:Dehydroepiandrosterone Sulfate; D016666:Fluvoxamine; D051057:Proto-Oncogene Proteins c-akt; D017480:Receptors, sigma; D012694:Serine; D000097605:Sigma-1 Receptor