{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T21:08:44Z","timestamp":1790716124955,"version":"4.1.0"},"reference-count":44,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2019,7,18]],"date-time":"2019-07-18T00:00:00Z","timestamp":1563408000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Glia"],"published-print":{"date-parts":[[2019,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The electrogenic sodium bicarbonate cotransporter 1, NBCe1 (SLC4A4), is the major bicarbonate transporter expressed in astrocytes. It is highly sensitive for bicarbonate and the main regulator of intracellular, extracellular, and synaptic pH, thereby modulating neuronal excitability. However, despite these essential functions, the molecular mechanisms underlying NBCe1\u2010mediated astrocytic response to extracellular pH changes are mostly unknown. Using primary mouse cortical astrocyte cultures, we investigated the effect of long\u2010term extracellular metabolic alkalosis on regulation of NBCe1 and elucidated the underlying molecular mechanisms by immunoblotting, biotinylation of surface proteins, intracellular H<jats:sup>+<\/jats:sup> recording using the H<jats:sup>+<\/jats:sup>\u2010sensitive dye 2\u2032,7\u2032\u2010bis\u2010(carboxyethyl)\u20105\u2010(and\u20106)\u2010carboxyfluorescein, and phosphoproteomic analysis. The results showed significant downregulation of NBCe1 activity following metabolic alkalosis without influencing protein abundance or surface expression of NBCe1. During alkalosis, the rate of intracellular H<jats:sup>+<\/jats:sup> changes upon challenging NBCe1 was decreased in wild\u2010type astrocytes, but not in cortical astrocytes from NBCe1\u2010deficient mice. Alkalosis\u2010induced decrease of NBCe1 activity was rescued after activation of mTOR signaling. Moreover, mass spectrometry revealed constitutively phosphorylated S255\u2010257 and mutational analysis uncovered these residues being crucial for NBCe1 transport activity. Our results demonstrate a novel mTOR\u2010regulated mechanism by which NBCe1 functional expression is regulated. Such mechanism likely applies not only for NBCe1 in astrocytes, but in epithelial cells as well.<\/jats:p>","DOI":"10.1002\/glia.23682","type":"journal-article","created":{"date-parts":[[2019,7,18]],"date-time":"2019-07-18T14:29:32Z","timestamp":1563460172000},"page":"2264-2278","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Functional expression of electrogenic sodium bicarbonate cotransporter 1 (NBCe1) in mouse cortical astrocytes is dependent on S255\u2010257 and regulated by mTOR"],"prefix":"10.1002","volume":"67","author":[{"given":"Shokoufeh","family":"Khakipoor","sequence":"first","affiliation":[{"name":"Department of Molecular Embryology, Faculty of Medicine Institute of Anatomy and Cell Biology, Albert\u2010Ludwigs\u2010Universit\u00e4t Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Giannaki","sequence":"additional","affiliation":[{"name":"Department of Molecular Embryology, Faculty of Medicine Institute of Anatomy and Cell Biology, Albert\u2010Ludwigs\u2010Universit\u00e4t Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shefeeq M.","family":"Theparambil","sequence":"additional","affiliation":[{"name":"Department of General Zoology, FB Biology University of Kaiserslautern  Kaiserslautern Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jana","family":"Zecha","sequence":"additional","affiliation":[{"name":"Chair of Proteomics and Bioanalytics Technical University of Munich  Freising Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard","family":"K\u00fcster","sequence":"additional","affiliation":[{"name":"Chair of Proteomics and Bioanalytics Technical University of Munich  Freising Germany"},{"name":"Bavarian Biomolecular Mass Spectrometry Center (BayBioMS) Technical University of Munich  Freising Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Heermann","sequence":"additional","affiliation":[{"name":"Department of Molecular Embryology, Faculty of Medicine Institute of Anatomy and Cell Biology, Albert\u2010Ludwigs\u2010Universit\u00e4t Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8763-7650","authenticated-orcid":false,"given":"Joachim W.","family":"Deitmer","sequence":"additional","affiliation":[{"name":"Department of General Zoology, FB Biology University of Kaiserslautern  Kaiserslautern Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0495-1597","authenticated-orcid":false,"given":"Eleni","family":"Roussa","sequence":"additional","affiliation":[{"name":"Department of Molecular Embryology, Faculty of Medicine Institute of Anatomy and Cell Biology, Albert\u2010Ludwigs\u2010Universit\u00e4t Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,7,18]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00010.2003"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.98.3.637"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainresrev.2009.10.006"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M607041200"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.4161\/auto.28363"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1402352111"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI80304"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2015111224"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2003.042226"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1221410110"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2004080667"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1199498"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/15440"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0169-328X(02)00559-4"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23168"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.051011"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.03.017"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1999.79.4.1431"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1471-4159.1997.69020581.x"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.85.3.890"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0138368"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22288"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.22388"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2012.04.018"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2013.04.008"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.2000475"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00023.2012"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuroscience.2007.02.061"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2003.12.099"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2012.10.003"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22814"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.126910"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1008705107"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.22829"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP273394"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP270086"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2377-13.2014"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M116.730143"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.1999.1484"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00094.2006"},{"key":"e_1_2_7_42_1","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aat5018"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI43475"},{"key":"e_1_2_7_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceca.2004.02.013"},{"key":"e_1_2_7_45_1","first-page":"193","article-title":"IRBIT coordinates epithelial fluid andHCO3\n                  \u2212 secretion by stimulating the transporters pNBC1 and CFTR in the murine pancreatic duct","volume":"119","author":"Yang D.","year":"2009","journal-title":"The Journal of Clinical Investigation"}],"container-title":["Glia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fglia.23682","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/glia.23682","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/glia.23682","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/glia.23682","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,4]],"date-time":"2023-09-04T20:45:40Z","timestamp":1693860340000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/glia.23682"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,18]]},"references-count":44,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2019,12]]}},"alternative-id":["10.1002\/glia.23682"],"URL":"https:\/\/doi.org\/10.1002\/glia.23682","archive":["Portico"],"relation":{},"ISSN":["0894-1491","1098-1136"],"issn-type":[{"value":"0894-1491","type":"print"},{"value":"1098-1136","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,7,18]]},"assertion":[{"value":"2018-05-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-07-03","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-07-18","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}