{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T01:01:45Z","timestamp":1787878905853,"version":"build-2784847793"},"reference-count":86,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T00:00:00Z","timestamp":1699833600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology of Japan","doi-asserted-by":"publisher","award":["21K06812"],"award-info":[{"award-number":["21K06812"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Modulation of the human Ether-\u00e0-go-go-Related Gene (hERG) channel, a crucial voltage-gated potassium channel in the repolarization of action potentials in ventricular myocytes of the heart, has significant implications on cardiac electrophysiology and can be either antiarrhythmic or proarrhythmic. For example, hERG channel blockade is a leading cause of long QT syndrome and potentially life-threatening arrhythmias, such as torsades de pointes. Conversely, hERG channel blockade is the mechanism of action of Class III antiarrhythmic agents in terminating ventricular tachycardia and fibrillation. In recent years, it has been recognized that less proarrhythmic hERG blockers with clinical potential or Class III antiarrhythmic agents exhibit, in addition to their hERG-blocking activity, a second action that facilitates the voltage-dependent activation of the hERG channel. This facilitation is believed to reduce the proarrhythmic potential by supporting the final repolarizing of action potentials. This review covers the pharmacological characteristics of hERG blockers\/facilitators, the molecular mechanisms underlying facilitation, and their clinical significance, as well as unresolved issues and requirements for research in the fields of ion channel pharmacology and drug-induced arrhythmias.<\/jats:p>","DOI":"10.3390\/ijms242216261","type":"journal-article","created":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T08:35:52Z","timestamp":1699864552000},"page":"16261","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Facilitation of hERG Activation by Its Blocker: A Mechanism to Reduce Drug-Induced Proarrhythmic Risk"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9680-2205","authenticated-orcid":false,"given":"Kazuharu","family":"Furutani","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Nishihama-Boji, Yamashiro-cho, Tokushima 770-8514, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1038\/nature04710","article-title":"hERG potassium channels and cardiac arrhythmia","volume":"440","author":"Sanguinetti","year":"2006","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/0092-8674(95)90340-2","article-title":"A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the IKr potassium channel","volume":"81","author":"Sanguinetti","year":"1995","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1126\/science.7604285","article-title":"HERG, a human inward rectifier in the voltage-gated potassium channel family","volume":"269","author":"Trudeau","year":"1995","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1152\/physrev.00036.2011","article-title":"hERG K(+) channels: Structure, function, and clinical significance","volume":"92","author":"Vandenberg","year":"2012","journal-title":"Physiol. 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