STAT3‐dependent regulation of the electrogenic Na+/HCO3− cotransporter 1 (NBCe1) functional expression in cortical astrocytes

• Published in: Journal of cellular physiology 2021-03, Vol.236 (3), p.2036-2050
• Main Authors: Giannaki, Marina, Schrödl‐Häußel, Magdalena, Khakipoor, Shokoufeh, Kirsch, Matthias, Roussa, Eleni
• Format: Article
• Language: English
• Subjects: acidosis; Astrocytes; astrogliosis; bicarbonate; Bicarbonates; Biotinylation; Brain; Brain injury; Flox; glial cells; Glial fibrillary acidic protein; Head injuries; Hippocampus; Homeostasis; Immunoblotting; pH effects; Phosphorylation; Protein expression; Proteins; signaling; Stat3 protein; Transcription
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.29990

The electrogenic Na+/HCO3− cotransporter (NBCe1) in astrocytes is crucial in regulation of acid–base homeostasis in the brain. Since many pathophysiological conditions in the brain have been associated with pH shifts we exposed primary mouse cortical and hippocampal astrocytes to prolonged low or high extracellular pH (pHo) at constant extracellular bicarbonate concentration and investigated activation of astrocytes and regulation of NBCe1 by immunoblotting, biotinylation of surface proteins, and intracellular H+ recordings. High pHo at constant extracellular bicarbonate caused upregulation of NBCe1 protein, surface expression and activity via upregulation of the astrocytic activation markers signal transducer and activator of transcription 3 (STAT3) signaling and glial fibrillary acidic protein expression. High pHo‐induced increased NBCe1 protein expression was prevented in astrocytes from Stat3flox/flox::GfapCre/+ mice. In vitro, basal and high pHo‐induced increased NBCe1 functional expression was impaired following inhibition of STAT3 phosphorylation. These results provide a novel regulation mode of NBCe1 protein and activity, highlight the importance of astrocyte reactivity on regulation of NBCe1 and implicate roles for NBCe1 in altering/modulating extracellular pH during development as well as of the microenvironment at sites of brain injuries and other pathophysiological conditions. Following an insult, NBCe1 in astrocytes can be regulated either via Src‐, ERK‐, and JNK‐signaling pathways and/or following activation of astrocytes through upregulation of pSTAT3 and glial fibrillary protein, resulting to upregulation of NBCe1 protein trafficking surface expression, and activity.