{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T19:50:04Z","timestamp":1776282604652,"version":"3.50.1"},"reference-count":49,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T00:00:00Z","timestamp":1741910400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010663","name":"H2020 European Research Council","doi-asserted-by":"publisher","award":["850622"],"award-info":[{"award-number":["850622"]}],"id":[{"id":"10.13039\/100010663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["2022\u201000844"],"award-info":[{"award-number":["2022\u201000844"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Congenital long QT syndrome (LQTS) involves genetic mutations affecting ion channels, leading to a prolonged QT interval and increased risk of potentially lethal ventricular arrhythmias. Mutations in the genes encoding K<jats:sub>V<\/jats:sub>7.1\/KCNE1 are the most frequent, with channel loss\u2010of\u2010function contributing to LQTS. The endocannabinoid N\u2010arachidonoyl\u2010L\u2010serine (ARA\u2010S) has been shown to facilitate activation of wild type K<jats:sub>V<\/jats:sub>7.1\/KCNE1 channels and to counteract a prolonged QT interval in isolated guinea pig hearts. In this study, we examine the ability of ARA\u2010S to facilitate activation of LQTS\u2010associated mutations, in various regions of the channel, and hence to counteract loss\u2010of\u2010function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>The two\u2010electrode voltage clamp technique on <jats:italic>Xenopus<\/jats:italic> oocytes expressing human K<jats:sub>V<\/jats:sub>7.1\/KCNE1 channels was used to investigate the effects of ARA\u2010S in 20 LQTS type 1\u2010associated mutations distributed across the channel. Thereafter, different electrophysiology was used to assess ARA\u2010S effects in mammalian cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>ARA\u2010S enhanced the function of all mutated channels by shifting V<jats:sub>50<\/jats:sub> and increasing current amplitude. However, the magnitude of effect varied, related to whether mutations were in one of the two putative ARA\u2010S binding sites on the channel as suggested by molecular dynamics simulations. ARA\u2010S displayed translational potential by facilitating channel opening in mammalian cells and shortening the action potential duration in cardiomyocytes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>This study demonstrates the rescuing capability of ARA\u2010S on a diverse set of LQTS mutants. These insights may aid in developing drug compounds using ARA\u2010S sites and mechanisms and guide interpretation of which LQTS mutants respond well to such compounds.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.70008","type":"journal-article","created":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T03:18:56Z","timestamp":1741922336000},"page":"2861-2877","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Rescue of loss\u2010of\u2010function long QT syndrome\u2010associated mutations in K<sub>V<\/sub>7.1\/KCNE1 by the endocannabinoid N\u2010arachidonoyl\u2010L\u2010serine (ARA\u2010S)"],"prefix":"10.1111","volume":"182","author":[{"given":"Irene","family":"Hiniesto\u2010I\u00f1igo","sequence":"first","affiliation":[{"name":"Department of Biomedical and Clinical Sciences Link\u00f6ping University  Link\u00f6ping Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akshay","family":"Sridhar","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences Link\u00f6ping University  Link\u00f6ping Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0649-4975","authenticated-orcid":false,"given":"Julien","family":"Louradour","sequence":"additional","affiliation":[{"name":"Translational Cardiology, Department of Physiology and Department of Cardiology, University of Bern University Hospital Bern  Bern Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alicia","family":"De la Cruz","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences Link\u00f6ping University  Link\u00f6ping Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siri","family":"Lundholm","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences Link\u00f6ping University  Link\u00f6ping Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amaia","family":"Jauregi\u2010Miguel","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Clinical Sciences Link\u00f6ping University  Link\u00f6ping Sweden"},{"name":"Chemical Biology Consortium Sweden (CBCS) SciLifeLab  Stockholm Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1785-5529","authenticated-orcid":false,"given":"Federica","family":"Giannetti","sequence":"additional","affiliation":[{"name":"Istituto Auxologico Italiano IRCCS Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4129-6632","authenticated-orcid":false,"given":"Luca","family":"Sala","sequence":"additional","affiliation":[{"name":"Istituto Auxologico Italiano IRCCS Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics  Milan Italy"},{"name":"Department of Biotechnology and Biosciences University of Milano\u2010Bicocca  Milan Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6999-841X","authenticated-orcid":false,"given":"Katja E.","family":"Odening","sequence":"additional","affiliation":[{"name":"Translational Cardiology, Department of Physiology and Department of Cardiology, University of Bern University Hospital Bern  Bern Switzerland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1688-2525","authenticated-orcid":false,"given":"H. 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