title: Inhibition of eNOS/sGC/PKG Pathway Decreases Akt Phosphorylation Induced by Kainic Acid in Mouse Hippocampus.
abstract: The serine/threonine kinase Akt has been shown to play a role of multiple cellular signaling pathways and act as a transducer of many functions initiated by growth factor receptors that activate phosphatidylinositol 3-kinase (PI3K). It has been reported that phosphorylated Akt activates eNOS resulting in the production of NO and that NO stimulates soluble guanylate cyclase (sGC), which results in accumulation of cGMP and subsequent activation of the protein kinase G (PKG). It has been also reported that PKG activates PI3K/Akt signaling. Therefore, it is possible that PI3K, Akt, eNOS, sGC, and PKG form a loop to exert enhanced and sustained activation of Akt. However, the existence of this loop in eNOS-expressing cells, such as endothelial cells or astrocytes, has not been reported. Thus, we examined a possibility that Akt phosphorylation might be enhanced via eNOS/sGC/PKG/PI3K pathway in astrocytes in vivo and in vitro. Phosphorylation of Akt was detected in astrocytes after KA treatment and was maintained up to 72 h in mouse hippocampus. 2 weeks after KA treatment, astrocytic Akt phosphorylation was normalized to control. The inhibition of eNOS, sGC, and PKG significantly decreased Akt and eNOS phosphorylation induced by KA in astrocytes. In contrast, the decreased phosphorylation of Akt and eNOS by eNOS inhibition was significantly reversed with PKG activation. The above findings in mouse hippocampus were also observed in primary astrocytes. These data suggest that Akt/eNOS/sGC/PKG/PI3K pathway may constitute a loop, resulting in enhanced and sustained Akt activation in astrocytes.
authors.affiliation: Department of Pharmacology, School of Medicine, Kangwon National University, Chunchon 200-701, Korea.
authors.forename: Sang Hyun
authors.initials: SH
authors.lastname: Lee
authors.forename: Jong Seon
authors.initials: JS
authors.lastname: Byun
authors.forename: Pil Jae
authors.initials: PJ
authors.lastname: Kong
authors.forename: Hee Jae
authors.initials: HJ
authors.lastname: Lee
authors.forename: Duk Kyung
authors.initials: DK
authors.lastname: Kim
authors.forename: Hae Sung
authors.initials: HS
authors.lastname: Kim
authors.forename: Jong-Hee
authors.initials: JH
authors.lastname: Sohn
authors.forename: Jae Jun
authors.initials: JJ
authors.lastname: Lee
authors.forename: So Young
authors.initials: SY
authors.lastname: Lim
authors.forename: Wanjoo
authors.initials: W
authors.lastname: Chun
authors.forename: Sung Soo
authors.initials: SS
authors.lastname: Kim