Fluoxetine induces alkalinization of astroglial cytosol through stimulation of sodium-hydrogen exchanger 1: dissection of intracellular signaling pathways

Frontiers in Cellular Neuroscience
Jienan RenLiang Peng

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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Citations

Sep 20, 2015·Progress in Neurobiology·Alexei VerkhratskyVedrana Montana
Dec 10, 2017·Journal of Neurochemistry·Maosheng XiaBaoman Li
Jan 20, 2018·Physiological Reviews·Alexei Verkhratsky, Maiken Nedergaard
Aug 6, 2019·Frontiers in Psychiatry·Luca SteardoPasquale De Fazio
May 29, 2020·Neuropharmacology·Matjaž StenovecRobert Zorec

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Methods Mentioned

BETA
immunoprecipitation
electrophoresis
GTPases

Software Mentioned

Window AlphaEase TM FC

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