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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 (pH<jats:sub>o<\/jats:sub>) at constant extracellular bicarbonate concentration and investigated activation of astrocytes and regulation of NBCe1 by immunoblotting, biotinylation of surface proteins, and intracellular H<jats:sup>+<\/jats:sup> recordings. High pH<jats:sub>o<\/jats:sub> 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 pH<jats:sub>o<\/jats:sub>\u2010induced increased NBCe1 protein expression was prevented in astrocytes from <jats:italic>Stat3<\/jats:italic><jats:sup><jats:italic>flox\/flox<\/jats:italic><\/jats:sup><jats:italic>::Gfap<\/jats:italic><jats:sup><jats:italic>Cre\/<\/jats:italic>+<\/jats:sup> mice. <jats:italic>In vitro<\/jats:italic>, basal and high pH<jats:sub>o<\/jats:sub>\u2010induced 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.<\/jats:p>","DOI":"10.1002\/jcp.29990","type":"journal-article","created":{"date-parts":[[2020,8,6]],"date-time":"2020-08-06T06:24:41Z","timestamp":1596695081000},"page":"2036-2050","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["STAT3\u2010dependent regulation of the electrogenic Na<sup>+\/<\/sup>HCO<sub>3<\/sub><sup>\u2212<\/sup> cotransporter 1 (NBCe1) functional expression in cortical astrocytes"],"prefix":"10.1002","volume":"236","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5761-4255","authenticated-orcid":false,"given":"Marina","family":"Giannaki","sequence":"first","affiliation":[{"name":"Department of Molecular Embryology, Medical Faculty, Institute of Anatomy and Cell Biology Albert\u2010Ludwigs\u2010Universit\u00e4t Freiburg  Freiburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magdalena","family":"Schr\u00f6dl\u2010H\u00e4u\u00dfel","sequence":"additional","affiliation":[{"name":"Department of Molecular Embryology, Medical Faculty, Institute of Anatomy and Cell Biology Albert\u2010Ludwigs\u2010Universit\u00e4t Freiburg  Freiburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shokoufeh","family":"Khakipoor","sequence":"additional","affiliation":[{"name":"Department of Molecular Embryology, Medical Faculty, Institute of Anatomy and Cell Biology Albert\u2010Ludwigs\u2010Universit\u00e4t Freiburg  Freiburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Kirsch","sequence":"additional","affiliation":[{"name":"Department of Neuroanatomy, 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, Medical Faculty, Institute of Anatomy and Cell Biology Albert\u2010Ludwigs\u2010Universit\u00e4t Freiburg  Freiburg Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2020,8,5]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.02166"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.278.5337.477"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/0003-2697(76)90527-3"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2015.03.020"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresrev.2009.10.006"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1709-08.2008"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1221410110"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0086851"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2004080667"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/15440"},{"key":"e_1_2_8_12_1","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1681\/ASN.V124713","article-title":"Novel nonsense mutation in the Na+\/HCO3\n                  \u2010 cotransporter gene (SLC4A4) in a patient with permanent isolated proximal renal tubular acidosis and bilateral glaucoma","volume":"12","author":"Garashi T.","year":"2001","journal-title":"Journal of the American Society of Nephrology"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1282"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neures.2007.06.1470"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23682"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23168"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm909"},{"key":"e_1_2_8_18_1","first-page":"890","article-title":"Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue","volume":"85","author":"McCarthy K. 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