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Electrophysiological characterization using heterologous expression systems has demonstrated that this R52L\n                      <jats:italic>GNB2<\/jats:italic>\n                      variant results in a larger G-protein\u2013activated K\n                      <jats:sup>+<\/jats:sup>\n                      (GIRK\/I\n                      <jats:sub>K, ACh<\/jats:sub>\n                      ) current. So far, this has not been functionally validated in patient-derived disease modelling using human induced pluripotent stem cell-derived cardiomyocytes (CM).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Here, we differentiated CMs derived from human induced pluripotent stem cells (hiPSC-CMs) of a patient carrying the pathogenic p.Arg52Leu\n                      <jats:italic>GNB2<\/jats:italic>\n                      variant (hiPSC\n                      <jats:sup>R52L<\/jats:sup>\n                      -CMs) and compared electrophysiological properties with those of two unrelated healthy hiPSC-CMs control lines. Retinoic acid (RA) treatment during the differentiation was used to generate hiPSC-CMs with robust acetylcholine-activated K\n                      <jats:sup>+<\/jats:sup>\n                      currents (I\n                      <jats:sub>K, ACh<\/jats:sub>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Patch-clamp experiments demonstrated that without GIRK channel stimulation the maximal diastolic potential (MDP) and spontaneous pacing rate did not differ between mutant and control cell lines and, moreover, a constitutively active I\n                      <jats:sub>K, ACh<\/jats:sub>\n                      was not observed. Upon stimulation of GIRK channels with carbachol (CCh), hiPSC\n                      <jats:sup>R52L<\/jats:sup>\n                      -CMs displayed an increased I\n                      <jats:sub>K, ACh<\/jats:sub>\n                      density, a more hyperpolarized MDP and a slower spontaneous activity as compared to both control hiPSC-CMs cell lines, thus explaining the bradycardia reported from patients carrying the R52L\n                      <jats:italic>GNB2<\/jats:italic>\n                      variant. Application of the specific I\n                      <jats:sub>K, ACh<\/jats:sub>\n                      blocker XAF-1407 rescued the phenotype.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      The reported, mutant\n                      <jats:italic>GNB2<\/jats:italic>\n                      in patient-derived CMs is associated with a gain-of function upon GIRK channel stimulation and thereby a larger I\n                      <jats:sub>K, ACh<\/jats:sub>\n                      , which could be potentially targeted and rescued by I\n                      <jats:sub>K, ACh<\/jats:sub>\n                      blockers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical trial number<\/jats:title>\n                    <jats:p>not applicable.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12872-026-06735-3","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T16:45:25Z","timestamp":1791218725000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The p.Arg52Leu variant in GNB2 causes a gain-of-function due to an increase of IK, ACh in stimulated hiPSC-CMs"],"prefix":"10.1186","volume":"26","author":[{"given":"Arie O.","family":"Verkerk","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Kayser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jassin","family":"Hamidi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven","family":"Dittmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Schulze-Bahr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,5]]},"reference":[{"key":"6735_CR1","doi-asserted-by":"publisher","unstructured":"Campos-Rios A, Rueda-Ruzafa L, Lamas JA. 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