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Using a mouse model of severe ischemic stroke, we identified a potentially targetable mechanism that promoted the cell surface localization of aquaporin 4 (AQP4) in perivascular astrocytic endfeet, which completely ensheathe the brain\u2019s capillaries. Cerebral ischemia increased the abundance of the heteromeric cation channel SUR1-TRPM4 and of the Na\n            <jats:sup>+<\/jats:sup>\n            \/Ca\n            <jats:sup>2+<\/jats:sup>\n            exchanger NCX1 in the endfeet of perivascular astrocytes. The influx of Na\n            <jats:sup>+<\/jats:sup>\n            through SUR1-TRPM4 induced Ca\n            <jats:sup>2+<\/jats:sup>\n            transport into cells through NCX1 operating in reverse mode, thus raising the intra-endfoot concentration of Ca\n            <jats:sup>2+<\/jats:sup>\n            . This increase in Ca\n            <jats:sup>2+<\/jats:sup>\n            stimulated calmodulin-dependent translocation of AQP4 to the plasma membrane and water influx, which led to cellular edema and brain swelling. Pharmacological inhibition or astrocyte-specific deletion of SUR1-TRPM4 or NCX1 reduced brain swelling and improved neurological function in mice to a similar extent as an AQP4 inhibitor and was independent of infarct size. Thus, channels in astrocyte endfeet could be targeted to reduce postischemic brain swelling in stroke patients.\n          <\/jats:p>","DOI":"10.1126\/scisignal.add6364","type":"journal-article","created":{"date-parts":[[2023,6,6]],"date-time":"2023-06-06T18:05:59Z","timestamp":1686074759000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":59,"title":["Cation flux through SUR1-TRPM4 and NCX1 in astrocyte endfeet induces water influx through AQP4 and brain swelling after ischemic stroke"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8547-9334","authenticated-orcid":true,"given":"Jesse A.","family":"Stokum","sequence":"first","affiliation":[{"name":"Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bosung","family":"Shim","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2477-0379","authenticated-orcid":true,"given":"Serban","family":"Negoita","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalya","family":"Tsymbalyuk","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orest","family":"Tsymbalyuk","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svetlana","family":"Ivanova","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaspar","family":"Keledjian","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3476-858X","authenticated-orcid":true,"given":"Joseph","family":"Bryan","sequence":"additional","affiliation":[{"name":"Pacific Northwest Diabetes Research Institute, Seattle, WA 98122, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2926-710X","authenticated-orcid":true,"given":"Mordecai P.","family":"Blaustein","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3047-7649","authenticated-orcid":true,"given":"Ruchira M.","family":"Jha","sequence":"additional","affiliation":[{"name":"Department of Neurology, Barrow Neurological Institute and St.\u00a0Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5922-7547","authenticated-orcid":true,"given":"Kristopher T.","family":"Kahle","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Volodymyr","family":"Gerzanich","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5373-1988","authenticated-orcid":true,"given":"J. 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