Abstract
Previously, we reported that fluoxetine acts on 5-HT2B receptor and induces epidermal growth factor receptor (EGFR) transactivation in astrocytes. Recently, we have found that chronic treatment with fluoxetine regulates Caveolin-1 (Cav-1)/PTEN/PI3K/AKT/glycogen synthase kinase 3β (GSK-3β) signaling pathway and glycogen content in primary cultures of astrocytes with bi-phasic concentration dependence. At low concentrations fluoxetine down-regulates Cav-1 gene expression, decreases membrane content of PTEN, increases PI3K activity and increases phosphorylation of GSK-3β and increases its activity; at high concentrations fluoxetine acts on PTEN/PI3K/AKT/GSK-3β in an inverse fashion. Here, we present the data indicating that acute treatment with fluoxetine at lower concentrations down-regulates c-Fos gene expression via PI3K/AKT signaling pathway; in contrast at higher concentrations fluoxetine up-regulates c-Fos gene expression via MAPK/extracellular-regulated kinase (ERK) signaling pathway. However, acute treatment with fluoxetine has no effect on Cav-1 protein content. Similarly, chronic effects of fluoxetine on Cav-1 gene expression are suppressed by inhibitor of PI3K at lower concentrations, but by inhibitor of MAPK at higher concentrations, indicating that the mechanism underlying bi-phasic regulation of Cav-1 gene expression by fluoxetine is opposing effects of PI3K/AKT and MAPK/ERK signal pathways on c-Fos gene expression. The effects of fluoxetine on Cav-1 gene expression at both lower and higher concentrations are abolished by AG1478, an inhibitor of EGFR, indicating the involvement of 5-HT2B receptor induced EGFR transactivation as we reported previously. However, PP1, an inhibitor of Src only abolished the effect by lower concentrations, suggesting the relevance of Src with PI3K/AKT signal pathway during activation of EGFR.
Highlights
Astroglial contribution to major depression does not involve astrogliosis and hypertrophy being mainly manifested by a decrease in astroglial numbers and their hypotrophy
No report exists about caveolin contribution to major depression the Cav-1 is linked to schizophrenia in both human polymorphism study (Najafipour et al, 2014) and in Cav-1 knockout animals (Allen et al, 2011)
Cav-1 in astrocytes is associated with reactivity (Niesman et al, 2014), with SorLA, a protein with sorting and trafficking functions and demonstrated relevance to Alzheimer’s disease (Salgado et al, 2012), with expression of connexin Cx43 (Strale et al, 2012), and with fatty acid-binding proteins (FABPs)-related signals (Kagawa et al, 2015)
Summary
Astroglial contribution to major depression ( to other psychiatric pathologies—see Verkhratsky et al, 2014) does not involve astrogliosis and hypertrophy being mainly manifested by a decrease in astroglial numbers and their hypotrophy. The 5-HT2B receptors are Gq/11 protein coupled and stimulation of these receptors generates diacyglycerol (DAG) and inositol 1,4,5-triphosphate (InsP3) The latter triggers an increase of intracellular calcium concentration ([Ca2+]i), which in turn activates Zn2+-dependent metalloproteinases and leads to shedding of growth factor(s) (for review see Peng and Huang, 2012). Phosphorylation of AKT and ERK occurs in a few minutes after fluoxetine administration, and lasts only for 40 min (Li et al, 2008; Bai et al, 2017) Both pathways may induce long-term modification of astrocytic functions via regulation of gene expression (Li et al, 2008; Hertz et al, 2012, 2014)
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