{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T00:56:11Z","timestamp":1773017771147,"version":"3.50.1"},"reference-count":51,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2017,8,7]],"date-time":"2017-08-07T00:00:00Z","timestamp":1502064000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["MOP 72911"],"award-info":[{"award-number":["MOP 72911"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2017,11]]},"abstract":"<jats:p>\n                    Human\n                    <jats:italic>ether\u2010a\u2010go\u2010go\u2010related<\/jats:italic>\n                    gene (\n                    <jats:italic>hERG<\/jats:italic>\n                    ) encodes the pore\u2010forming subunit of the rapidly activating delayed rectifier potassium current (I\n                    <jats:sub>Kr<\/jats:sub>\n                    ) potassium channel, which is important for cardiac repolarization. Impairment of hERG function is the primary cause of acquired long QT syndrome, which predisposes individuals to cardiac arrhythmias and sudden death. Patients with hypoxia due to conditions such as cardiac ischemia or obstructive sleep apnea display increased incidence of cardiac arrhythmias and sudden death. We sought to understand the mechanisms that underlie hypoxia\u2010associated cardiac arrhythmias. Using cell biology and electro\u2010physiologic techniques, we found that hypoxic culture of hERG\u2010expressing human embryonic kidney (HEK) cells and neonatal rat cardiomyocytes reduced hERG current\/\n                    <jats:italic>I<\/jats:italic>\n                    <jats:sub>Kr<\/jats:sub>\n                    and mature ERG channel expression with a concomitant increase in calpain expression. Calpain was actively released into the extracellular milieu and degraded cell\u2010surface hERG. In contrast to hERG, the ether\u2010a\u2010go\u2010go (EAG) channel was not reduced by hypoxic culture. By making chimeric channels between hERG and EAG, we identified that hypoxia\u2010induced calpain degraded hERG by targeting its extracellular S5\u2010pore linker. The scorpion toxin BeKm\u20101, which is known to selectively bind to the S5\u2010pore linker of hERG, prevented hypoxia\u2010induced hERG reduction. Our data provide novel information about hypoxia\u2010mediated hERG dysfunction and may have biological and clinical implications in hypoxia\u2010associated diseases.\u2014Lamothe, S. M., Song, W., Guo, J., Li, W., Yang, T., Baranchuk, A., Graham, C. H., Zhang, S. Hypoxia reduces mature hERG channels through calpain up\u2010regulation. FASEB J. 31, 5068\u20135077 (2017).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201700255r","type":"journal-article","created":{"date-parts":[[2017,8,8]],"date-time":"2017-08-08T10:15:34Z","timestamp":1502187334000},"page":"5068-5077","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Hypoxia reduces mature hERG channels through calpain up\u2010regulation"],"prefix":"10.1096","volume":"31","author":[{"given":"Shawn M.","family":"Lamothe","sequence":"first","affiliation":[{"name":"Department of Biomedical and Molecular Sciences Queen\u2019s University Kingston Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"WonJu","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Molecular Sciences Queen\u2019s University Kingston Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Molecular Sciences Queen\u2019s University Kingston Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wentao","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Molecular Sciences Queen\u2019s University Kingston Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tonghua","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Molecular Sciences Queen\u2019s University Kingston Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adrian","family":"Baranchuk","sequence":"additional","affiliation":[{"name":"Department of Medicine, Kingston General Hospital Queen\u2019s University Kingston Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles H.","family":"Graham","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Molecular Sciences Queen\u2019s University Kingston Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shetuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Molecular Sciences Queen\u2019s University Kingston Ontario Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,8,7]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature04710"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90340-2"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.7604285"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1989.69.4.1049"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)61622-0"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2010.12.030"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jelectrocard.2012.03.003"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(99)00132-7"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1001\/archinternmed.2009.138"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2006.11.035"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00512.2010"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/18.20.5540"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.82.3.386"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.107.120931"},{"key":"e_1_2_8_16_1","doi-asserted-by":"crossref","first-page":"2004","DOI":"10.1016\/j.hrthm.2016.06.019","article-title":"Febrile temperature facilitates hERG\/I\n                  Kr degradation through an altered K+ dependence.","volume":"13","author":"Zhao Y.","year":"2016","journal-title":"Heart Rhythm"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00679.2005"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(98)77782-3"},{"key":"e_1_2_8_19_1","doi-asserted-by":"crossref","first-page":"H77","DOI":"10.1152\/ajpheart.00008.2002","article-title":"Role of glycosylation in cell surface expression and stability of HERG potassium channels.","volume":"283","author":"Gong Q.","year":"2002","journal-title":"Am. 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