{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T05:26:31Z","timestamp":1791264391761,"version":"4.1.0"},"reference-count":67,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T00:00:00Z","timestamp":1697587200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Leducq Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Mutations in the KCNJ5 gene, encoding one of the major subunits of cardiac G-protein-gated inwardly rectifying K+ (GIRK) channels, have been recently linked to inherited forms of sinus node dysfunction. Here, the pathogenic mechanism of the W101C KCNJ5 mutation underlying sinus bradycardia in a patient-derived cellular disease model of sinus node dysfunction (SND) was investigated. A human-induced pluripotent stem cell (hiPSCs) line of a mutation carrier was generated, and CRISPR\/Cas9-based gene targeting was used to correct the familial mutation as a control line. Both cell lines were further differentiated into cardiomyocytes (hiPSC-CMs) that robustly expressed GIRK channels which underly the acetylcholine-regulated K+ current (IK,ACh). hiPSC-CMs with the W101C KCNJ5 mutation (hiPSCW101C-CM) had a constitutively active IK,ACh under baseline conditions; the application of carbachol was able to increase IK,ACh, further indicating that not all available cardiac GIRK channels were open at baseline. Additionally, hiPSCW101C-CM had a more negative maximal diastolic potential (MDP) and a slower pacing frequency confirming the bradycardic phenotype. Of note, the blockade of the constitutively active GIRK channel with XAF-1407 rescued the phenotype. These results provide further mechanistic insights and may pave the way for the treatment of SND patients with GIRK channel dysfunction.<\/jats:p>","DOI":"10.3390\/ijms242015290","type":"journal-article","created":{"date-parts":[[2023,10,18]],"date-time":"2023-10-18T09:55:06Z","timestamp":1697622906000},"page":"15290","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The W101C KCNJ5 Mutation Induces Slower Pacing by Constitutively Active GIRK Channels in hiPSC-Derived Cardiomyocytes"],"prefix":"10.3390","volume":"24","author":[{"given":"Anne","family":"Kayser","sequence":"first","affiliation":[{"name":"Institute for Genetics of Heart Diseases (IfGH), University Hospital M\u00fcnster, 48149 M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5829-3676","authenticated-orcid":false,"given":"Sven","family":"Dittmann","sequence":"additional","affiliation":[{"name":"Institute for Genetics of Heart Diseases (IfGH), University Hospital M\u00fcnster, 48149 M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8344-1095","authenticated-orcid":false,"given":"Tomo","family":"\u0160ari\u0107","sequence":"additional","affiliation":[{"name":"Center for Physiology and Pathophysiology, Institute for Neurophysiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50931 Cologne, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giulia","family":"Mearini","sequence":"additional","affiliation":[{"name":"Institute of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2140-834X","authenticated-orcid":false,"given":"Arie O.","family":"Verkerk","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Department of Experimental Cardiology, Amsterdam University Medical Centers, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6884-2501","authenticated-orcid":false,"given":"Eric","family":"Schulze-Bahr","sequence":"additional","affiliation":[{"name":"Institute for Genetics of Heart Diseases (IfGH), University Hospital M\u00fcnster, 48149 M\u00fcnster, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,10,18]]},"reference":[{"key":"ref_1","first-page":"179","article-title":"Sinus Node Dysfunction","volume":"104","author":"Hawks","year":"2021","journal-title":"Am. 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