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In this study, we generated and characterized a mouse model of ATS1 carrying the trafficking-deficient mutant Kir2.1<jats:sup>\u0394314-315<\/jats:sup> channel. The mutant mouse recapitulates the electrophysiological phenotype of ATS1, with QT prolongation exacerbated by flecainide or isoproterenol, drug-induced QRS prolongation, increased vulnerability to reentrant arrhythmias and multifocal discharges resembling catecholaminergic polymorphic ventricular tachycardia (CPVT). Kir2.1<jats:sup>\u0394314-315<\/jats:sup> cardiomyocytes display significantly reduced inward rectifier K<jats:sup>+<\/jats:sup> and Na<jats:sup>+<\/jats:sup> currents, depolarized resting membrane potential and prolonged action potentials. We show that, in wild-type mouse cardiomyocytes and skeletal muscle cells, Kir2.1 channels localize to sarcoplasmic reticulum (SR) microdomains, contributing to intracellular Ca<jats:sup>2+<\/jats:sup> homeostasis. Kir2.1<jats:sup>\u0394314-315<\/jats:sup> cardiomyocytes exhibit defective SR Kir2.1 localization and function, as intact and permeabilized Kir2.1<jats:sup>\u0394314-315<\/jats:sup> cardiomyocytes display abnormal spontaneous Ca<jats:sup>2+<\/jats:sup> release events. Overall, defective Kir2.1 channel function at the sarcolemma and the SR explain the life-threatening arrhythmias in ATS1 and its overlap with CPVT.<\/jats:p>","DOI":"10.1038\/s44161-022-00145-2","type":"journal-article","created":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T16:03:51Z","timestamp":1666022631000},"page":"900-917","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Kir2.1 dysfunction at the sarcolemma and the sarcoplasmic reticulum causes arrhythmias in a mouse model of Andersen\u2013Tawil syndrome type 1"],"prefix":"10.1038","volume":"1","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9952-6947","authenticated-orcid":false,"given":"\u00c1lvaro","family":"Mac\u00edas","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1230-5293","authenticated-orcid":false,"given":"Andr\u00e9s","family":"Gonz\u00e1lez-Guerra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5011-2786","authenticated-orcid":false,"given":"Ana I.","family":"Moreno-Manuel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco M.","family":"Cruz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lilian K.","family":"Guti\u00e9rrez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nieves","family":"Garc\u00eda-Quint\u00e1ns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Roche-Molina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francisco","family":"Berm\u00fadez-Jim\u00e9nez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0125-7209","authenticated-orcid":false,"given":"Vicente","family":"Andr\u00e9s","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Linarejos","family":"Vera-Pedrosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Mart\u00ednez-Carrascoso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan A.","family":"Bernal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0080-3500","authenticated-orcid":false,"given":"Jos\u00e9","family":"Jalife","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,10,17]]},"reference":[{"key":"145_CR1","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/S0092-8674(01)00342-7","volume":"105","author":"NM Plaster","year":"2001","unstructured":"Plaster, N. 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