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.

Acetylcholine Promotes Ca2+and NO-Oscillations in Adipocytes Implicating Ca2+→NO→cGMP→cADP-ribose→Ca2+ Positive Feedback Loop - Modulatory Effects of Norepinephrine and Atrial Natriuretic Peptide

“…This may be phosphorylation of eNOS by CaMKII or by AMPK [104], [105] which is in turn activated by Ca-calmodulin dependent kinase kinase (CaMKK) [106], or even an activation of PKB by CaMKII [107], [108].…”

“…Furthermore, it is known that NO and cGMP may bring about the phosphorylation of PKB by CaMKII [107], [108], allowing for the possible functioning of yet another long PFL(7):…”

Nitric oxide increases the migratory activity of non-small cell lung cancer cells via AKT-mediated integrin αv and β1 upregulation

“…Also, AKT has been shown to act as a downstream phosphorylation target of PKG [29]. In order to unravel the mechanism by which NO regulates integrin expression, the activation of PKG, AKT and FAK in response to NO treatment was assessed in NSCLC-derived H460, H292 and H23 cells.…”

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“…Sodium nitroprusside significantly induced the phosphorylation of ERK1/2 and JNK MAPK, Akt and CREB in N2a cells. The phosphorylation of Akt was promoted by peroxynitrite produced in SNP‐induction and it may result in the up‐regulation of prosurvival factor and neuroprotective factor expression (Delgado‐Esteban et al ., ; Lee et al ., ). Cryptotanshinone significantly inhibited SNP‐induced phosphorylation of ERK1/2 and JNK MAPK, but further induced the phosphorylation of Akt and CREB.…”