Fluvoxamine and sigma-1 receptor agonists dehydroepiandrosterone (DHEA)-sulfate induces the Ser473-phosphorylation of Akt-1 in PC12 cells.
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.
Nakano
Miho
M
Department of Neuropsychiatry, St. Marianna University School of Medicine, 2-16-1 Sugao Miyamae-ku Kawasaki, Kanagawa 216-8511, Japan.
Osada
Kenichi
K
Misonoo
Atsushi
A
Fujiwara
Keisuke
K
Takahashi
Miho
M
Ogawa
Yuriko
Y
Haga
Toshiaki
T
Kanai
Shigeto
S
Tanaka
Daisuke
D
Sasuga
Yasuo
Y
Yanagida
Takuyoh
T
Asakura
Mikio
M
Yamaguchi
Noboru
N
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
D019314:Dehydroepiandrosterone Sulfate; D016666:Fluvoxamine; D051057:Proto-Oncogene Proteins c-akt; D017480:Receptors, sigma; D012694:Serine; D000097605:Sigma-1 Receptor