{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T04:20:43Z","timestamp":1782188443051,"version":"3.54.5"},"reference-count":65,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2023,2,20]],"date-time":"2023-02-20T00:00:00Z","timestamp":1676851200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL136389"],"award-info":[{"award-number":["R01HL136389"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL131517"],"award-info":[{"award-number":["R01HL131517"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL089598"],"award-info":[{"award-number":["R01HL089598"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL163277"],"award-info":[{"award-number":["R01HL163277"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000780","name":"European Commission","doi-asserted-by":"publisher","award":["965286"],"award-info":[{"award-number":["965286"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2023,7]]},"abstract":"Abstract<\/jats:title>Cardiac electrophysiology is regulated by continuous trafficking and internalization of ion channels occurring over minutes to hours. Kv<\/jats:sub>11.1 (also known as hERG) underlies the rapidly activating delayed\u2010rectifier K+<\/jats:sup> current (I<\/jats:italic>Kr<\/jats:sub>), which plays a major role in cardiac ventricular repolarization. Experimental characterization of the distinct temporal effects of genetic and acquired modulators on channel trafficking and gating is challenging. Computer models are instrumental in elucidating these effects, but no currently available model incorporates ion\u2010channel trafficking. Here, we present a novel computational model that reproduces the experimentally observed production, forward trafficking, internalization, recycling and degradation of Kv<\/jats:sub>11.1 channels, as well as their modulation by temperature, pentamidine, dofetilide and extracellular K+<\/jats:sup>. The acute effects of these modulators on channel gating were also incorporated and integrated with the trafficking model in the O'Hara\u2013Rudy human ventricular cardiomyocyte model. Supraphysiological dofetilide concentrations substantially increased Kv<\/jats:sub>11.1 membrane levels while also producing a significant channel block. However, clinically relevant concentrations did not affect trafficking. Similarly, severe hypokalaemia reduced Kv<\/jats:sub>11.1 membrane levels based on long\u2010term culture data, but had limited effect based on short\u2010term data. By contrast, clinically relevant elevations in temperature acutely increased I<\/jats:italic>Kr<\/jats:sub> due to faster kinetics, while after 24\u00a0h, I<\/jats:italic>Kr<\/jats:sub> was decreased due to reduced Kv<\/jats:sub>11.1 membrane levels. The opposite was true for lower temperatures. Taken together, our model reveals a complex temporal regulation of cardiac electrophysiology by temperature, hypokalaemia, and dofetilide through competing effects on channel gating and trafficking, and provides a framework for future studies assessing the role of impaired trafficking in cardiac arrhythmias.\nimage<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec>Key points<\/jats:title>\nKv<\/jats:sub>11.1 channels underlying the rapidly activating delayed\u2010rectifier K+<\/jats:sup> current are important for ventricular repolarization and are continuously shuttled from the cytoplasm to the plasma membrane and back over minutes to hours.<\/jats:p><\/jats:list-item>\nKv<\/jats:sub>11.1 gating and trafficking are modulated by temperature, drugs and extracellular K+<\/jats:sup> concentration but experimental characterization of their combined effects is challenging. Computer models may facilitate these analyses, but no currently available model incorporates ion\u2010channel trafficking.<\/jats:p><\/jats:list-item>\nWe introduce a new two\u2010state ion\u2010channel trafficking model able to reproduce a wide range of experimental data, along with the effects of modulators of Kv<\/jats:sub>11.1 channel functioning and trafficking.<\/jats:p><\/jats:list-item>\nThe model reveals complex dynamic regulation of ventricular repolarization by temperature, extracellular K+<\/jats:sup> concentration and dofetilide through opposing acute (millisecond) effects on Kv<\/jats:sub>11.1 gating and long\u2010term (hours) modulation of Kv<\/jats:sub>11.1 trafficking.<\/jats:p><\/jats:list-item>\nThis in silico<\/jats:italic> trafficking framework provides a tool to investigate the roles of acute and long\u2010term processes on arrhythmia promotion and maintenance.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp283976","type":"journal-article","created":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T10:23:58Z","timestamp":1675851838000},"page":"2711-2731","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["In silico<\/i> analysis of the dynamic regulation of cardiac electrophysiology by Kv<\/sub>11.1 ion\u2010channel trafficking"],"prefix":"10.1113","volume":"601","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"}]},{"given":"Ada\u00efa","family":"Grundland","sequence":"additional","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"},{"name":"Department of Data Science and Knowledge Engineering, Faculty of Science and Engineering Maastricht University 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 and Biophysics Baylor College of Medicine Houston Texas United States of America"},{"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"}]},{"given":"Paul G. A.","family":"Volders","sequence":"additional","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\/0000-0002-1418-108X","authenticated-orcid":false,"given":"Jordi","family":"Heijman","sequence":"additional","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"}]}],"member":"311","published-online":{"date-parts":[[2023,2,20]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2013.07.030"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2020.04.003"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2125.2000.00243.x"},{"issue":"7","key":"e_1_2_6_5_1","first-page":"2552","article-title":"Fever\u2010induced QTc prolongation and ventricular arrhythmias in individuals with type 2 congenital long QT syndrome","volume":"118","author":"Amin A. S.","year":"2008","journal-title":"Journal of Clinical Investigation"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.570200"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms6535"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.e13-07-0417"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2018.10.046"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00808"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.115.001357"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells10092417"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(00)00293-5"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pbiomolbio.2015.12.008"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2013.03.008"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.254367"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.111.075135"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-022-00759-w"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jelectrocard.2017.04.006"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00616"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M309087200"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-42331-6"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2018.06.013"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI39027"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.253351"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.117.005776"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP271404"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.120.316710"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvab138"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2013.11.004"},{"key":"e_1_2_6_31_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1003202"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2018.00397"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2009.05.021"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20130328"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/europace\/eup376"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2015.00026"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.812572"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1647"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.215970"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2016.07.002"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1109370109"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2018.00958"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajem.2011.02.019"},{"key":"e_1_2_6_44_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1002061"},{"key":"e_1_2_6_45_1","doi-asserted-by":"publisher","DOI":"10.1111\/jce.13259"},{"key":"e_1_2_6_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2007.05.008"},{"key":"e_1_2_6_47_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.016217"},{"key":"e_1_2_6_48_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M708999200"},{"key":"e_1_2_6_49_1","doi-asserted-by":"publisher","DOI":"10.1124\/mol.119.118190"},{"key":"e_1_2_6_50_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1323541111"},{"key":"e_1_2_6_51_1","doi-asserted-by":"publisher","DOI":"10.1111\/anec.12723"},{"key":"e_1_2_6_52_1","doi-asserted-by":"publisher","DOI":"10.1159\/000430353"},{"key":"e_1_2_6_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.joa.2015.11.009"},{"key":"e_1_2_6_54_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00406.2012"},{"key":"e_1_2_6_55_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2008.10.056"},{"key":"e_1_2_6_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2019.104444"},{"key":"e_1_2_6_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0707618"},{"key":"e_1_2_6_58_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2018.01254"},{"key":"e_1_2_6_59_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00596.2005"},{"key":"e_1_2_6_60_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12208"},{"key":"e_1_2_6_61_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00246-019-02151-x"},{"key":"e_1_2_6_62_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2005.03.008"},{"key":"e_1_2_6_63_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.113.007765"},{"key":"e_1_2_6_64_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP272942"},{"key":"e_1_2_6_65_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2016.06.019"},{"key":"e_1_2_6_66_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(98)77782-3"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP283976","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1113\/JP283976","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP283976","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,19]],"date-time":"2023-08-19T15:09:30Z","timestamp":1692457770000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP283976"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,20]]},"references-count":65,"journal-issue":{"issue":"13","published-print":{"date-parts":[[2023,7]]}},"alternative-id":["10.1113\/JP283976"],"URL":"https:\/\/doi.org\/10.1113\/jp283976","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,20]]},"assertion":[{"value":"2022-10-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-01-30","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-02-20","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}