{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T17:38:40Z","timestamp":1761673120393,"version":"build-2065373602"},"reference-count":48,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T00:00:00Z","timestamp":1759449600000},"content-version":"vor","delay-in-days":2,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Journal Cellular Physiology"],"published-print":{"date-parts":[[2025,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    As a major modulator of cardiac function, intracellular pH (pH\n                    <jats:sub>i<\/jats:sub>\n                    ) is tightly controlled by sarcolemmal acid\u2013base transporters to within narrow limits (7.1\u20137.3). Na\n                    <jats:sup>+<\/jats:sup>\n                    \/H\n                    <jats:sup>+<\/jats:sup>\n                    exchanger (NHE1) and Na\n                    <jats:sup>+<\/jats:sup>\n                    \/HCO\n                    <jats:sub>3<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    cotransporter (NBC) are the main acid\u2010extruding membrane proteins; the latter is further subdivided into electrogenic (NBCe1\/NBCe2) and electroneutral (NBCn1) isoforms. In the underperfused heart, acid disturbances are often accompanied by hypoxia, but their interplay on cardiac NBC activity is unknown. Here, we studied the effect of acute (1\u2009mM dithionite and 100% N\n                    <jats:sub>2<\/jats:sub>\n                    , 10\u2009min) and long\u2010term hypoxia (1% O\n                    <jats:sub>2<\/jats:sub>\n                    , 48\u2009h) on sarcolemmal NBC activity using fluorimetric assays in mouse atrial\u2010derived HL\u20101 cells and primary rat cardiomyocytes. NBCe1 and NBCn1 transcripts were detected in HL\u20101 cells. Ensemble NBC activity, defined as the HCO\n                    <jats:sub>3<\/jats:sub>\n                    <jats:sup>\u2212<\/jats:sup>\n                    \u2010dependent acid\u2010extrusion flux, was promptly inhibited under acute anoxia. In contrast, pH\n                    <jats:sub>i<\/jats:sub>\n                    \u2010sensitivity of NBC flux was increased after long\u2010term hypoxia, likely an adaptive response. This increase was not due to buffering capacity changes but was mimicked by dimethyloxalylglycine (1\u2009mM, DMOG), which stabilizes hypoxia inducible factor under normoxic conditions. Hypoxia affected neither NBCn1 nor NBCe1 protein levels, indicating a modulatory effect on transporter activity. The contribution of electrogenic (NBCe1) and electroneutral (NBCn1) isoforms, dissected from fluxes generated under hyperkalemia, showed that long\u2010term hypoxia selectively raised NBCn1 activity. This effect was blocked by U0126, an inhibitor of extracellular signal\u2010regulated kinase 1\/2, implicating phosphorylation. Our results show that acute anoxia and prolonged hypoxia regulate NBC\u2010dependent flux by distinct mechanisms ostensibly to retain pH control under the combination of acidosis and hypoxia.\n                  <\/jats:p>","DOI":"10.1002\/jcp.70097","type":"journal-article","created":{"date-parts":[[2025,10,3]],"date-time":"2025-10-03T10:51:20Z","timestamp":1759488680000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hypoxia Increases Sarcolemmal Na\n                    <sup>+<\/sup>\n                    \/HCO\n                    <sub>3<\/sub>\n                    <sup>\u2212<\/sup>\n                    Cotransport Activity via an ERK1\/2\u2010Dependent Pathway in Cardiac HL\u20101 Cell Line"],"prefix":"10.1002","volume":"240","author":[{"given":"G\u00fcl","family":"\u015eim\u015fek","sequence":"first","affiliation":[{"name":"Department of Biophysics Faculty of Medicine, Ankara University Ankara T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pawel","family":"Swietach","sequence":"additional","affiliation":[{"name":"Department of Physiology, Anatomy, and Genetics University of Oxford Oxford UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3050-6443","authenticated-orcid":false,"given":"Hilmi Burak","family":"Kandilci","sequence":"additional","affiliation":[{"name":"Department of Biophysics Faculty of Medicine, Ankara University Ankara 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