Fluvoxamine and sigma-1 receptor agonists dehydroepiandrosterone (DHEA)-sulfate induces the Ser super(473)-phosphorylation of Akt-1 in PC12 cells

• Published in: Life sciences (1973) Vol. 86; no. 9-10; pp. 309 - 314
• Main Authors: Nakano, Miho, Osada, Kenichi, Misonoo, Atsushi, Fujiwara, Keisuke, Takahashi, Miho, Ogawa, Yuriko, Haga, Toshiaki, Kanai, Shigeto, Tanaka, Daisuke, Sasuga, Yasuo, Yanagida, Takuyoh, Asakura, Mikio, Yamaguchi, Noboru
• Format: Journal Article
• Language: English
• Published: 27.02.2010
• ISSN: 0024-3205
• DOI: 10.1016/j.lfs.2009.11.017

Aims - 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 sub(3)/Ca super(2+) pathway. Furthermore, the PLC-. gamma /IP sub(3)/Ca super(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. Main 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. Key findings - Treatment with 10 mu M and 100 mu M FLV of PC12 cells stimulated a 2.4- and 3.8-fold maximal increase in Ser super(473)-phosphorylated Akt-1 levels at 40 min, respectively. Treatment with 50 ng/ml BDNF also stimulated Ser super(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. Significance - 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.