Signal Transduction in Astrocytes during Chronic or Acute Treatment with Drugs (SSRIs, Antibipolar Drugs, GABA-ergic Drugs, and Benzodiazepines) Ameliorating Mood Disorders
Figure 1
Schematic illustration of pathways leading to stimulation of ERK and AKT phosphorylation by fluoxetine in astrocytes. Fluoxetine binds to receptors. The activation of the receptors in turn induces an enhancement of protein kinase C (PKC) activity and of intracellular Ca2+ concentration by Ca2+ release from intracellular stores. The latter activates Zn-dependent metalloproteinases (MMPs) and leads to shedding of growth factor(s). The released epidermal growth factor receptor (EGFR) ligand stimulates phosphorylation of the EGFR. The downstream target of EGFR, extracellular-regulated kinase (ERK) (shown in blue) is phosphorylated via the Ras/Raf/MEK pathway, and AKT is phosphorylated via PI3K pathway. During chronic fluoxetine administration, inhibitors (shown in yellow) of the receptor (SB204741), or siRNA against this receptor, of PKC (GF 109293X), of intracellular Ca2+ homeostasis (BAPTA/AM, an intracellular Ca2+ chelator), of Zn-dependent metalloproteinases (GM6001), of the receptor-tyrosine kinase of the EGFR (AG1478), of ERK phosphorylation (U0126, a mitogen-activated kinase (MEK) inhibitor), or of the AKT pathway (LY294002, a PI3K inhibitor) prevent changes in gene expression and editing. PIK3 catalyzes the formation of PIP3 from PIP2, from Hertz et al. [5].
