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Plasma membrane (PM) injury causes a pathological calcium influx. Here, we show that the ER helps clear this surge in cytoplasmic calcium through an ER-resident calcium pump, SERCA, and a calcium-activated ion channel, Anoctamin 5 (ANO5). SERCA imports calcium into the ER, and ANO5 supports this by maintaining electroneutrality of the ER lumen through anion import. Preventing either of these transporter activities causes cytosolic calcium overload and disrupts PM repair (PMR). ANO5 deficit in limb girdle muscular dystrophy 2L (LGMD2L) patient cells compromises their cytosolic and ER calcium homeostasis. By generating a mouse model of LGMD2L, we find that PM injury causes cytosolic calcium overload and compromises the ability of ANO5-deficient myofibers to repair. Addressing calcium overload in ANO5-deficient myofibers enables them to repair, supporting the requirement of the ER in calcium homeostasis in injured cells and facilitating PMR.<\/jats:p>","DOI":"10.1083\/jcb.202006035","type":"journal-article","created":{"date-parts":[[2021,3,10]],"date-time":"2021-03-10T14:27:07Z","timestamp":1615386427000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":24,"title":["Endoplasmic reticulum maintains ion homeostasis required for plasma membrane repair"],"prefix":"10.1083","volume":"220","author":[{"given":"Goutam","family":"Chandra","sequence":"first","affiliation":[{"name":"Center of Genetic Medicine Research, Children\u2019s National Health System, Washington, DC 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sen Chandra","family":"Sreetama","sequence":"additional","affiliation":[{"name":"Center of Genetic Medicine Research, Children\u2019s National Health System, Washington, DC 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davi A.G.","family":"M\u00e1zala","sequence":"additional","affiliation":[{"name":"Center of Genetic Medicine Research, Children\u2019s National Health System, Washington, DC 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7419-140X","authenticated-orcid":true,"given":"Karine","family":"Charton","sequence":"additional","affiliation":[{"name":"G\u00e9n\u00e9thon, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, U951, INTEGRARE Research Unit, University Paris-Saclay, Evry, France 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack H.","family":"VanderMeulen","sequence":"additional","affiliation":[{"name":"Center of Genetic Medicine Research, Children\u2019s National Health System, Washington, DC 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6505-446X","authenticated-orcid":true,"given":"Isabelle","family":"Richard","sequence":"additional","affiliation":[{"name":"G\u00e9n\u00e9thon, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale, U951, INTEGRARE Research Unit, University Paris-Saclay, Evry, France 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5992-5185","authenticated-orcid":true,"given":"Jyoti K.","family":"Jaiswal","sequence":"additional","affiliation":[{"name":"Center of Genetic Medicine Research, Children\u2019s National Health System, Washington, DC 1"},{"name":"Department of Genomics and Precision Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC 3"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2021,3,10]]},"reference":[{"key":"2023072403300581400_bib1","doi-asserted-by":"publisher","first-page":"14485","DOI":"10.1073\/pnas.1018266108","article-title":"Parallel adaptive feedback enhances reliability of the Ca2+ signaling system","volume":"108","author":"Abell","year":"2011","journal-title":"Proc. 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