Fluoxetine induces alkalinization of astroglial cytosol through stimulation of sodium-hydrogen exchanger 1: dissection of intracellular signaling pathways
Abstract
Clinical evidence suggest astrocytic abnormality in major depression (MD) while treatment with anti-psychotic drugs affects astroglial functions. Astroglial cells are involved in pH homeostasis of the brain by transporting protons (through sodium-proton transporter 1, NHE1, glutamate transporters EAAT1/2 and proton-lactate co-transporter MCT1) and bicarbonate (through the sodium-bicarbonate co-transporter NBC or the chloride-bicarbonate exchanger AE). Here we show that chronic treatment with fluoxetine increases astroglial pH i by stimulating NHE1-mediated proton extrusion. At a clinically relevant concentration of 1 μM, fluoxetine significantly increased astroglial pH i from 7.05 to 7.34 after 3 weeks and from 7.18 to 7.58 after 4 weeks of drug treatment. Stimulation of NHE1 is a result of transporter phosphorylation mediated by several intracellular signaling cascades that include MAPK/ERK1/2, PI3K/AKT and ribosomal S6 kinase (RSK). Fluoxetine stimulated phosphorylation of ERK1/2, AKT and RSK in a concentration dependent manner. Positive crosstalk exists between two signal pathways, MAPK/ERK1/2 and PI3K/AKT activated by fluoxetine since ERK1/2 phosphrylation could be abolished by inhibitors of PI3K, LY294002 and AKT, tricirib...Continue Reading
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