{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T09:25:22Z","timestamp":1783070722536,"version":"3.54.6"},"reference-count":52,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2025,7,20]],"date-time":"2025-07-20T00:00:00Z","timestamp":1752969600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,7,20]],"date-time":"2025-07-20T00:00:00Z","timestamp":1752969600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2026,7]]},"abstract":"\n Abstract<\/jats:title>\n \n Small\u2010conductance calcium\u2010activated potassium (SK) channels are promising targets for atrial\u2010specific antiarrhythmic therapies, with evidence suggesting tachycardia\u2010dependent SK\u2010channel upregulation. However, the dynamics of SK\u2010channel gating and trafficking in human atrial electrophysiology remain unclear because of experimental limitations, including the availability of human cardiomyocytes and long patch clamp experiments. Although computational models help explore these mechanisms, none integrate SK\u2010channel trafficking. In the present study, we expanded our K\n v<\/jats:sub>\n 11.1 trafficking model to simulate rate\u2010dependent SK\u2010channel trafficking in a human atrial cardiomyocyte model. Calibrated against experimental data, our model replicates time\u2010 and rate\u2010dependent SK\u2010channel function, allowing simulations of SK\u2010channel trafficking and its effects on action potentials. Tachypacing at 5\u00a0Hz increased SK\u2010channel density, enhancing SK current and shortening action potential duration, with or without calcium buffering. Two\u2010dimensional tissue simulations with physiological calcium handling showed that tachycardia increased re\u2010entry duration and ectopic activity. SK\u2010channel inhibition reduced re\u2010entry duration but promoted ectopic activity, suggesting a reduction in atrial fibrillation burden rather than complete elimination. Our novel computational model highlights SK channels\u2019 role in re\u2010entry\u2010promoting effects of short atrial tachycardia episodes, offering insights into early atrial fibrillation progression and potential antiarrhythmic strategies.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n Small\u2010conductance calcium\u2010activated potassium (SK) channels have emerged as potential targets for atrial\u2010specific antiarrhythmic therapies, especially in atrial fibrillation (AF).<\/jats:p>\n <\/jats:list-item>\n \n Emerging evidence suggests that tachycardia\u2010induced SK\u2010channel trafficking can regulate cardiac cellular electrophysiology over minutes, but investigating its impact on arrhythmogenesis in humans is experimentally challenging.<\/jats:p>\n <\/jats:list-item>\n \n \n We adapted our recent\n in silico<\/jats:italic>\n K\n v<\/jats:sub>\n 11.1 trafficking model to simulate SK\u2010channel trafficking and incorporated it into a human atrial cardiomyocyte model, which was calibrated based on experimental results.\n <\/jats:p>\n <\/jats:list-item>\n \n Tachypacing at 5\u00a0Hz led to a substantial increase in SK channel\u2010density at the membrane, resulting in enhanced SK current and a reduction in action potential duration.<\/jats:p>\n <\/jats:list-item>\n \n \n 2\u2010D tissue simulations demonstrated that rapid pacing promoted both re\u2010entry and ectopic (triggered) activity. Blocking SK channels reduced re\u2010entry duration but increased ectopic activity, suggesting that SK channel inhibition could decrease AF burden, but may not eliminate AF\n per se<\/jats:italic>\n .\n <\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp288659","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T04:25:00Z","timestamp":1753071900000},"page":"5355-5377","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Computational modelling of the pro\u2010 and antiarrhythmic effects of atrial high rate\u2010dependent trafficking of small\u2010conductance calcium\u2010activated potassium channels"],"prefix":"10.1113","volume":"604","author":[{"given":"Stefan","family":"Meier","sequence":"first","affiliation":[{"name":"Department of Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Faculty of Health, Medicine, and Life Sciences Maastricht University and Maastricht University Medical Center Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4612-117X","authenticated-orcid":false,"given":"Dobromir","family":"Dobrev","sequence":"additional","affiliation":[{"name":"Institute of Pharmacology, West German Heart and Vascular Center University of Duisburg\u2010Essen Essen Germany"},{"name":"Department of Molecular Physiology & Biophysics Baylor College of Medicine Houston Texas USA"},{"name":"Department of Medicine and Research Center Montreal Heart Institute and Universit\u00e9 de Montr\u00e9al Montr\u00e9al Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2652-1598","authenticated-orcid":false,"given":"Paul G. 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