{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T05:26:30Z","timestamp":1791264390149,"version":"4.1.0"},"reference-count":49,"publisher":"The Company of Biologists","issue":"7","license":[{"start":{"date-parts":[[2020,9,3]],"date-time":"2020-09-03T00:00:00Z","timestamp":1599091200000},"content-version":"vor","delay-in-days":430,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100002996","name":"Dutch Heart Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002996","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003180","name":"Academisch Medisch Centrum","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003180","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,7,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>Mutations in GNB5, encoding the G-protein \u03b25 subunit (G\u03b25), have recently been linked to a multisystem disorder that includes severe bradycardia. Here, we investigated the mechanism underlying bradycardia caused by the recessive p.S81L G\u03b25 variant. Using CRISPR\/Cas9-based targeting, we generated an isogenic series of human induced pluripotent stem cell (hiPSC) lines that were either wild type, heterozygous or homozygous for the GNB5 p.S81L variant. These were differentiated into cardiomyocytes (hiPSC-CMs) that robustly expressed the acetylcholine-activated potassium channel [I(KACh); also known as IK,ACh]. Baseline electrophysiological properties of the lines did not differ. Upon application of carbachol (CCh), homozygous p.S81L hiPSC-CMs displayed an increased acetylcholine-activated potassium current (IK,ACh) density and a more pronounced decrease of spontaneous activity as compared to wild-type and heterozygous p.S81L hiPSC-CMs, explaining the bradycardia in homozygous carriers. Application of the specific I(KACh) blocker XEN-R0703 resulted in near-complete reversal of the phenotype. Our results provide mechanistic insights and proof of principle for potential therapy in patients carrying GNB5 mutations.<\/jats:p>\n               <jats:p>This article has an associated First Person interview with the first author of the paper.<\/jats:p>","DOI":"10.1242\/dmm.037994","type":"journal-article","created":{"date-parts":[[2019,6,17]],"date-time":"2019-06-17T16:39:03Z","timestamp":1560789543000},"source":"Crossref","is-referenced-by-count":27,"title":["Genetic variation in <i>GNB5<\/i> causes bradycardia by augmenting the cholinergic response via increased acetylcholine-activated potassium current (<i>I<\/i>K,ACh)"],"prefix":"10.1242","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4570-5234","authenticated-orcid":false,"given":"Christiaan C.","family":"Veerman","sequence":"first","affiliation":[{"name":"Amsterdam UMC, University of Amsterdam 1 , Department of Experimental Cardiology , , 1105 AZ Amsterdam , The Netherlands"},{"name":"Heart Center 1 , 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Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rianne","family":"Wolswinkel","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, University of Amsterdam 1 , Department of Experimental Cardiology , , 1105 AZ Amsterdam , The Netherlands"},{"name":"Heart Center 1 , Department of Experimental Cardiology , , 1105 AZ Amsterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariam","family":"Hababa","sequence":"additional","affiliation":[{"name":"Hubrecht Institute 3 , 3584 CT Utrecht , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teun P.","family":"de Boer","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht 2 Department of Medical Physiology , , 3584 CX Utrecht , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaomei","family":"Guan","sequence":"additional","affiliation":[{"name":"Technische Universit\u00e4t Dresden 5 Department of Pharmacology and Toxicology , , 01062 Dresden , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0947-2808","authenticated-orcid":false,"given":"James","family":"Milnes","sequence":"additional","affiliation":[{"name":"Xention Ltd 6 , Cambridge CB22 3EG , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6017-3796","authenticated-orcid":false,"given":"Elisabeth M.","family":"Lodder","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, University of Amsterdam 1 , Department of Experimental Cardiology , , 1105 AZ Amsterdam , The Netherlands"},{"name":"Heart Center 1 , Department of Experimental Cardiology , , 1105 AZ Amsterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9418-0422","authenticated-orcid":false,"given":"Jeroen","family":"Bakkers","sequence":"additional","affiliation":[{"name":"University Medical Center Utrecht 2 Department of Medical Physiology , , 3584 CX Utrecht , The Netherlands"},{"name":"Hubrecht Institute 3 , 3584 CT Utrecht , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arie O.","family":"Verkerk","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, University of Amsterdam 1 , Department of Experimental Cardiology , , 1105 AZ Amsterdam , The Netherlands"},{"name":"Heart Center 1 , Department of Experimental Cardiology , , 1105 AZ Amsterdam , The Netherlands"},{"name":"Amsterdam UMC, University of Amsterdam 4 , Department of Medical Biology , , 1105 AZ Amsterdam , The Netherlands"},{"name":"Heart Failure Research Center 4 , Department of Medical Biology , , 1105 AZ Amsterdam , The 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