{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T23:36:07Z","timestamp":1787009767461,"version":"build-2736575974"},"reference-count":47,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2018,10,5]],"date-time":"2018-10-05T00:00:00Z","timestamp":1538697600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001732","name":"Danmarks Grundforskningsfond","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001732","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006442","name":"Det Sundhedsvidenskabelige Fakultet, K\u00f8benhavns Universitet","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006442","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007460","name":"Arvid Nilssons Fond","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007460","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004963","name":"Seventh Framework Programme","doi-asserted-by":"publisher","award":["FP7\/2007-2013"],"award-info":[{"award-number":["FP7\/2007-2013"]}],"id":[{"id":"10.13039\/501100004963","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000783","name":"Research Executive Agency","doi-asserted-by":"publisher","award":["608765"],"award-info":[{"award-number":["608765"]}],"id":[{"id":"10.13039\/501100000783","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003554","name":"Lundbeckfonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003554","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL079275"],"award-info":[{"award-number":["HL079275"]}],"id":[{"id":"10.13039\/100000002","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":[[2019,2]]},"abstract":"ABSTRACT<\/jats:title>\n \n KCNE5<\/jats:italic>\n is an X\u2010linked gene encoding KCNE5, an ancillary subunit to voltage\u2010gated potassium (K\n v<\/jats:sub>\n ) channels. Human\n KCNE5<\/jats:italic>\n mutations are associated with atrial fibrillation (AF)\u2013 and Brugada syndrome (BrS)\u2013induced cardiac arrhythmias that can arise from increased potassium current in cardiomyocytes. Seeking to establish underlying molecular mechanisms, we created and studied\n Kcne5<\/jats:italic>\n knockout (\n \n Kcne5\n \u2212\/0<\/jats:sup>\n <\/jats:italic>\n ) mice. Intracardiac ECG revealed that\n Kcne5<\/jats:italic>\n deletion caused ventricular premature beats, increased susceptibility to induction of polymorphic ventricular tachycardia (60\n vs<\/jats:italic>\n . 24% in\n \n Kcne5\n +\/0<\/jats:sup>\n <\/jats:italic>\n mice), and 10% shorter ventricular refractory period.\n Kcne5<\/jats:italic>\n deletion increased mean ventricular myocyte K\n v<\/jats:sub>\n current density in the apex and also in the subpopulation of septal myocytes that lack fast transient outward current (\n I<\/jats:italic>\n to,f<\/jats:sub>\n ). The current increases arose from an apex\u2010specific increase in slow transient outward current\u20101 (\n I<\/jats:italic>\n Kslow,1<\/jats:sub>\n ) (conducted by K\n v<\/jats:sub>\n 1.5) and\n I<\/jats:italic>\n to,f<\/jats:sub>\n (conducted by K\n V<\/jats:sub>\n 4) and an increase in\n I<\/jats:italic>\n Kslow,2<\/jats:sub>\n (conducted by K\n v<\/jats:sub>\n 2.1) in both apex and septum. Kcne5 protein localized to the intercalated discs in ventricular myocytes, where K\n V<\/jats:sub>\n 2.1 was also detected in both\n Kcne5<\/jats:italic>\n \u2212\/0<\/jats:sup>\n and\n Kcne5<\/jats:italic>\n +\/0<\/jats:sup>\n mice. In HL\u20101 cardiac cells and human embryonic kidney cells, KCNE5 and K\n V<\/jats:sub>\n 2.1 colocalized at the cell surface, but predominantly in intracellular vesicles, suggesting that\n Kcne<\/jats:italic>\n 5 deletion increases\n I<\/jats:italic>\n K,slow2<\/jats:sub>\n by reducing K\n V<\/jats:sub>\n 2.1 intracellular sequestration. The human AF\u2010associated mutation KCNE5\u2010L65F negative shifted the voltage dependence of K\n V<\/jats:sub>\n 2.1\u2010KCNE5 channels, increasing their maximum current density >2\u2010fold, whereas BrS\u2010associated KCNE5 mutations produced more subtle negative shifts in K\n V<\/jats:sub>\n 2.1 voltage dependence. The findings represent the first reported native role for Kcne5 and the first demonstrated Kcne regulation of K\n V<\/jats:sub>\n 2.1 in mouse heart. Increased K\n V<\/jats:sub>\n current is a manifestation of\n KCNE5<\/jats:italic>\n disruption that is most likely common to both mouse and human hearts, providing a plausible mechanistic basis for human\n KCNE5<\/jats:italic>\n \u2010linked AF and BrS.\u2014David, J.\u2010P., Lisewski, U., Crump, S. M., Jepps, T. A., Bocksteins, E., Wilck, N., Lossie, J., Roepke, T. K., Schmitt, N., Abbott, G. W. Deletion in mice of X\u2010linked, Brugada syndrome\u2014and atrial fibrillation\u2013associated Kcne5 augments ventricular KV currents and predisposes to ventricular arrhythmia. FASEB J. 33, 2537\u20132552 (2019).\n www.fasebj.org<\/jats:ext-link>\n <\/jats:p>","DOI":"10.1096\/fj.201800502r","type":"journal-article","created":{"date-parts":[[2018,10,5]],"date-time":"2018-10-05T14:51:10Z","timestamp":1538751070000},"page":"2537-2552","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Deletion in mice of X\u2010linked, Brugada syndrome\u2013and atrial fibrillation\u2013associated\n Kcne5<\/i>\n augments ventricular K\n v<\/sub>\n currents and predisposes to ventricular arrhythmia"],"prefix":"10.1096","volume":"33","author":[{"given":"Jens-Peter","family":"David","sequence":"first","affiliation":[{"name":"Danish National Research Foundation Centre for Cardiac Arrhythmia University of Copenhagen Copenhagen Denmark"},{"name":"Department of Biomedical Sciences University of Copenhagen Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ulrike","family":"Lisewski","sequence":"additional","affiliation":[{"name":"Medical Clinic and Polyclinic for Cardiology and Angiology Charit\u00e9 Medical University of Berlin Berlin Germany"},{"name":"Experimental and Clinical Research Center (ECRC) Charit\u00e9 Medical University of Berlin Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawn M.","family":"Crump","sequence":"additional","affiliation":[{"name":"Bioelectricity Laboratory Department of Physiology and Biophysics University of California, Irvine Irvine California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas A.","family":"Jepps","sequence":"additional","affiliation":[{"name":"Danish National Research Foundation Centre for Cardiac Arrhythmia University of Copenhagen Copenhagen Denmark"},{"name":"Department of Biomedical Sciences University of Copenhagen Copenhagen 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Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Torsten K.","family":"Roepke","sequence":"additional","affiliation":[{"name":"Medical Clinic and Polyclinic for Cardiology and Angiology Charit\u00e9 Medical University of Berlin Berlin Germany"},{"name":"Experimental and Clinical Research Center (ECRC) Charit\u00e9 Medical University of Berlin Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole","family":"Schmitt","sequence":"additional","affiliation":[{"name":"Danish National Research Foundation Centre for Cardiac Arrhythmia University of Copenhagen Copenhagen Denmark"},{"name":"Department of Biomedical Sciences University of Copenhagen Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geoffrey W.","family":"Abbott","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Biophysics, Physiology, and Pharmacology Department for Biomedical Sciences University of Antwerp Antwerp 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