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Here, we describe amammalian target of rapamycin (mTOR)\u2010dependent and NBCe1\u2010mediated astroglial response to extracellular acidosis. Using primary mouse cortical astrocytes, we investigated the effect of long\u2010term extracellular metabolic acidosis on regulation of NBCe1 and elucidated the underlying molecular mechanisms by immunoblotting, biotinylation of surface proteins, intracellular H\n                    <jats:sup>+<\/jats:sup>\n                    recording using the H\n                    <jats:sup>+<\/jats:sup>\n                    \u2010sensitive dye 2\u2032,7\u2032\u2010bis\u2010(carboxyethyl)\u20105\u2010(and\u20106)\u2010carboxyfluorescein, and phosphoproteomic analysis. The results showed significant increase of NBCe1\u2010mediated recovery of intracellular pH from acidification in WT astrocytes, but not in cortical astrocytes from NBCe1\u2010deficient mice. Acidosis\u2010induced upregulation of NBCe1 activity was prevented following inhibition of mTOR signaling by rapamycin. Yet, during acidosis or following exposure of astrocytes to rapamycin, surface protein abundance of NBCe1 remained \u2010unchanged. Mutational analysis in HeLa cells suggested that NBCe1 activity was dependent on phosphorylation state of Ser\n                    <jats:sup>245<\/jats:sup>\n                    , a residue conserved in all NBCe1 variants. Moreover, phosphorylation state of Ser\n                    <jats:sup>245<\/jats:sup>\n                    is regulated by mTOR and is inversely correlated with NBCe1 transport activity. Our results identify pSer\n                    <jats:sup>245<\/jats:sup>\n                    as a novel regulator of NBCe1 functional expression. We propose that context\u2010dependent and mTOR\u2010mediated multisite phosphorylation of serine residues of NBCe1 is likely to be a potent mechanism contributing to the response of astrocytes to acid\/base challenges during pathophysiological conditions.\n                  <\/jats:p>","DOI":"10.1002\/jcp.30601","type":"journal-article","created":{"date-parts":[[2021,10,16]],"date-time":"2021-10-16T11:34:29Z","timestamp":1634384069000},"page":"1372-1388","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Regulation of electrogenic Na\n                    <sup>+<\/sup>\n                    \/HCO\n                    <sub>3<\/sub>\n                    <sup>\u2212<\/sup>\n                    cotransporter 1 (NBCe1) function and its dependence on m\u2010TOR mediated phosphorylation of Ser\n                    <sup>245<\/sup>"],"prefix":"10.1002","volume":"237","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5761-4255","authenticated-orcid":false,"given":"Marina","family":"Giannaki","sequence":"first","affiliation":[{"name":"Department of Molecular Embryology Institute of Anatomy and Cell Biology, Medical Faculty, Albert\u2010Ludwigs\u2010Universit\u00e4t Freiburg Freiburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina","family":"Ludwig","sequence":"additional","affiliation":[{"name":"Bavarian Center for Biomolecular Mass Spectrometry (BayBioMS) Technical University of Munich (TUM) Freising Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephan","family":"Heermann","sequence":"additional","affiliation":[{"name":"Department of Molecular Embryology Institute of Anatomy and Cell Biology, Medical Faculty, Albert\u2010Ludwigs\u2010Universit\u00e4t Freiburg Freiburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0495-1597","authenticated-orcid":false,"given":"Eleni","family":"Roussa","sequence":"additional","affiliation":[{"name":"Department of Molecular Embryology Institute of Anatomy and Cell Biology, Medical Faculty, Albert\u2010Ludwigs\u2010Universit\u00e4t Freiburg Freiburg 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