{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:58:09Z","timestamp":1787032689995,"version":"build-2736575974"},"reference-count":31,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2023,6,23]],"date-time":"2023-06-23T00:00:00Z","timestamp":1687478400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,6,23]],"date-time":"2023-06-23T00:00:00Z","timestamp":1687478400000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,6,23]],"date-time":"2023-06-23T00:00:00Z","timestamp":1687478400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100019180","name":"HORIZON EUROPE European Research Council","doi-asserted-by":"publisher","award":["850622"],"award-info":[{"award-number":["850622"]}],"id":[{"id":"10.13039\/100019180","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"publisher","award":["2021-01885"],"award-info":[{"award-number":["2021-01885"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL131461"],"award-info":[{"award-number":["R01HL131461"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,6,22]]},"abstract":"<jats:p>\n                    Voltage-gated potassium (K\n                    <jats:sub>V<\/jats:sub>\n                    ) channels are important regulators of cellular excitability and control action potential repolarization in the heart and brain. K\n                    <jats:sub>V<\/jats:sub>\n                    channel mutations lead to disordered cellular excitability. Loss-of-function mutations, for example, result in membrane hyperexcitability, a characteristic of epilepsy and cardiac arrhythmias. Interventions intended to restore K\n                    <jats:sub>V<\/jats:sub>\n                    channel function have strong therapeutic potential in such disorders. Polyunsaturated fatty acids (PUFAs) and PUFA analogues comprise a class of K\n                    <jats:sub>V<\/jats:sub>\n                    channel activators with potential applications in the treatment of arrhythmogenic disorders such as long QT syndrome (LQTS). LQTS is caused by a loss-of-function of the cardiac I\n                    <jats:sub>Ks<\/jats:sub>\n                    channel \u2013 a tetrameric potassium channel complex formed by K\n                    <jats:sub>V<\/jats:sub>\n                    7.1 and associated KCNE1 protein subunits. We have discovered a set of aromatic PUFA analogues that produce robust activation of the cardiac I\n                    <jats:sub>Ks<\/jats:sub>\n                    channel, and a unique feature of these PUFA analogues is an aromatic, tyrosine head group. We determine the mechanisms through which tyrosine PUFA analogues exert strong activating effects on the I\n                    <jats:sub>Ks<\/jats:sub>\n                    channel by generating modified aromatic head groups designed to probe cation\u2013pi interactions, hydrogen bonding, and ionic interactions. We found that tyrosine PUFA analogues do not activate the I\n                    <jats:sub>Ks<\/jats:sub>\n                    channel through cation\u2013pi interactions, but instead do so through a combination of hydrogen bonding and ionic interactions.\n                  <\/jats:p>","DOI":"10.7554\/elife.85773","type":"journal-article","created":{"date-parts":[[2023,6,23]],"date-time":"2023-06-23T14:16:05Z","timestamp":1687529765000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.85773","source":"Crossref","is-referenced-by-count":16,"title":["Mechanistic insights into robust cardiac IKs potassium channel activation by aromatic polyunsaturated fatty acid analogues"],"prefix":"10.7554","volume":"12","author":[{"given":"Briana M","family":"Bohannon","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02dgjyy92","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Physiology and Biophysics, Miller School of Medicine, University of Miami","place":["Miami, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica J","family":"Jowais","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02dgjyy92","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Physiology and Biophysics, Miller School of Medicine, University of Miami","place":["Miami, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leif","family":"Nyberg","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02dgjyy92","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Physiology and Biophysics, Miller School of Medicine, University of Miami","place":["Miami, United States"]},{"id":[{"id":"https:\/\/ror.org\/05ynxx418","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biomedical and Clinical Sciences, Link\u00f6ping University","place":["Link\u00f6ping, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vanessa","family":"Olivier-Meo","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02dgjyy92","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Physiology and Biophysics, Miller School of Medicine, University of Miami","place":["Miami, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Corradi","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03yjb2x39","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biological Sciences and Centre for Molecular Simulation, University of Calgary","place":["Calgary, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5507-0688","authenticated-orcid":true,"given":"D Peter","family":"Tieleman","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03yjb2x39","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biological Sciences and Centre for Molecular Simulation, University of Calgary","place":["Calgary, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8493-0114","authenticated-orcid":true,"given":"Sara I","family":"Liin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05ynxx418","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Biomedical and Clinical Sciences, Link\u00f6ping University","place":["Link\u00f6ping, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1688-2525","authenticated-orcid":true,"given":"H Peter","family":"Larsson","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02dgjyy92","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Physiology and Biophysics, Miller School of Medicine, University of Miami","place":["Miami, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2023,6,23]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"1753","DOI":"10.1007\/s00424-018-2193-1","article-title":"Transcripts of Kv7.1 and Mink channels and slow delayed rectifier K+ current (I Ks) are expressed in Zebrafish (Danio rerio) heart","volume":"470","author":"Abramochkin","year":"2018","journal-title":"Pfl\u00fcgers Archiv - European Journal of Physiology"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1038\/384078a0","article-title":"K(V)Lqt1 and Isk (minK) proteins associate to form the I(Ks) cardiac potassium current","volume":"384","author":"Barhanin","year":"1996","journal-title":"Nature"},{"key":"bib3","doi-asserted-by":"publisher","DOI":"10.1111\/apha.13186","article-title":"\u03a9-6 and \u03a9-9 polyunsaturated fatty acids with double bonds near the Carboxyl head have the highest affinity and largest effects on the cardiac Iks potassium channel","volume":"225","author":"Bohannon","year":"2019","journal-title":"Acta Physiologica"},{"key":"bib4","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.201912396","article-title":"Polyunsaturated fatty acids produce a range of activators for heterogeneous IKs channel dysfunction","volume":"152","author":"Bohannon","year":"2020","journal-title":"The Journal of General Physiology"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"2242","DOI":"10.1529\/biophysj.108.130757","article-title":"Lipoelectric modification of ion channel voltage gating by polyunsaturated fatty acids","volume":"95","author":"B\u00f6rjesson","year":"2008","journal-title":"Biophysical Journal"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1085\/jgp.201110599","article-title":"An electrostatic potassium channel opener targeting the final voltage sensor transition","volume":"137","author":"B\u00f6rjesson","year":"2011","journal-title":"The Journal of General Physiology"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"741","DOI":"10.1085\/jgp.200308927","article-title":"Molecular movement of the voltage sensor in a K channel","volume":"122","author":"Broomand","year":"2003","journal-title":"The Journal of General Physiology"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"1504S","DOI":"10.1093\/jn\/137.6.1504S","article-title":"Cation-pi interactions involving aromatic amino acids","volume":"137","author":"Dougherty","year":"2007","journal-title":"The Journal of Nutrition"},{"key":"bib9","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00043","article-title":"Actions and mechanisms of polyunsaturated fatty acids on voltage-Gated ion channels","volume":"8","author":"Elinder","year":"2017","journal-title":"Frontiers in Physiology"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/biology6010007","article-title":"Cardiac Channelopathies and sudden death: Recent clinical and genetic advances","volume":"6","author":"Fern\u00e1ndez-Falgueras","year":"2017","journal-title":"Biology"},{"key":"bib11","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2021.167035","article-title":"Cation-\u03a0 interactions and their functional roles in membrane proteins","volume":"433","author":"Infield","year":"2021","journal-title":"Journal of Molecular Biology"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"8755","DOI":"10.1074\/jbc.R100062200","article-title":"The Biochemistry of N-3 polyunsaturated fatty acids","volume":"277","author":"Jump","year":"2002","journal-title":"The Journal of Biological Chemistry"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"E6751","DOI":"10.1073\/pnas.1719105115","article-title":"S4\u2013S5 Linker movement during activation and inactivation in voltage-Gated K+ channels","volume":"115","author":"Kalstrup","year":"2018","journal-title":"PNAS"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3389\/fphys.2020.00641","article-title":"Polyunsaturated fatty acids as Modulators of Kv7 channels","volume":"11","author":"Larsson","year":"2020","journal-title":"Frontiers in Physiology"},{"key":"bib15","doi-asserted-by":"publisher","first-page":"5714","DOI":"10.1073\/pnas.1503488112","article-title":"Polyunsaturated fatty acid analogs act Antiarrhythmically on the cardiac Iks channel","volume":"112","author":"Liin","year":"2015","journal-title":"PNAS"},{"key":"bib16","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.20272","article-title":"Fatty acid analogue N-Arachidonoyl Taurine restores function of IKs channels with diverse long QT mutations","volume":"5","author":"Liin","year":"2016","journal-title":"eLife"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"2908","DOI":"10.1016\/j.celrep.2018.08.031","article-title":"Mechanisms underlying the dual effect of polyunsaturated fatty acid analogs on Kv7.1","volume":"24","author":"Liin","year":"2018","journal-title":"Cell Reports"},{"key":"bib18","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2012.00245","article-title":"Effects of N-3 polyunsaturated fatty acids on cardiac ion channels","volume":"3","author":"Moreno","year":"2012","journal-title":"Frontiers in Physiology"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1093\/cvr\/cvu250","article-title":"Marine N-3 Pufas modulate Iks gating, Channel expression, and location in membrane Microdomains","volume":"105","author":"Moreno","year":"2015","journal-title":"Cardiovascular Research"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"1205","DOI":"10.1152\/physrev.00002.2005","article-title":"Molecular physiology of cardiac Repolarization","volume":"85","author":"Nerbonne","year":"2005","journal-title":"Physiological Reviews"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1085\/jgp.200609612","article-title":"The role of S4 charges in voltage-dependent and voltage-independent Kcnq1 potassium channel complexes","volume":"129","author":"Panaghie","year":"2007","journal-title":"The Journal of General Physiology"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1085\/jgp.201311036","article-title":"Asymmetric functional contributions of acidic and aromatic side chains in sodium channel voltage-sensor domains","volume":"143","author":"Pless","year":"2014","journal-title":"The Journal of General Physiology"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1056\/NEJMcp0706513","article-title":"Long-QT syndrome","volume":"358","author":"Roden","year":"2008","journal-title":"New England Journal of Medicine"},{"key":"bib24","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2012.00063","article-title":"Regulation of voltage-activated K(+) channel gating by Transmembrane \u0392 subunits","volume":"3","author":"Sun","year":"2012","journal-title":"Frontiers in Pharmacology"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.1016\/j.cell.2017.05.019","article-title":"Cryo-EM structure of a Kcnq1\/Cam complex reveals insights into congenital long QT syndrome","volume":"169","author":"Sun","year":"2017","journal-title":"Cell"},{"key":"bib26","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1016\/j.hlc.2016.01.020","article-title":"Update on the diagnosis and management of familial long QT syndrome","volume":"25","author":"Waddell-Smith","year":"2016","journal-title":"Heart, Lung and Circulation"},{"key":"bib27","doi-asserted-by":"publisher","first-page":"34069","DOI":"10.1074\/jbc.273.51.34069","article-title":"Mink-Kvlqt1 fusion proteins, evidence for multiple Stoichiometries of the assembled I(sK) channel","volume":"273","author":"Wang","year":"1998","journal-title":"The Journal of Biological Chemistry"},{"key":"bib28","first-page":"1171","article-title":"Long QT syndrome","volume":"63","author":"Watanabe","year":"2005","journal-title":"Nippon Rinsho"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"3599","DOI":"10.1016\/j.bpj.2010.10.018","article-title":"Kcne1 Remodels the voltage sensor of Kv7.1 to modulate channel function","volume":"99","author":"Wu","year":"2010","journal-title":"Biophysical Journal"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1085\/jgp.112.6.665","article-title":"Single-channel properties of Iks potassium channels","volume":"112","author":"Yang","year":"1998","journal-title":"Journal of General Physiology"},{"key":"bib31","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.202012850","article-title":"Identification of Pufa interaction sites on the cardiac potassium channel Kcnq1","volume":"153","author":"Yazdi","year":"2021","journal-title":"The Journal of General Physiology"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/85773\/elife-85773-v2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/85773\/elife-85773-v2.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/85773","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T21:14:40Z","timestamp":1697058880000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/85773"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,23]]},"references-count":31,"alternative-id":["10.7554\/eLife.85773"],"URL":"https:\/\/doi.org\/10.7554\/elife.85773","archive":["CLOCKSS"],"relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2023.01.12.523777","asserted-by":"subject"},{"id-type":"doi","id":"10.1101\/2023.01.12.523777","asserted-by":"object"}],"has-review":[{"id-type":"doi","id":"10.7554\/eLife.85773.sa0","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.85773.sa1","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.85773.sa2","asserted-by":"object"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,23]]},"assertion":[{"value":"single anonymised","name":"peer_review_transparency","label":"Peer review transparency","group":{"name":"peer_review_taxonomy"}},{"value":"other reviewer(s), editor","name":"peer_review_interaction","label":"Peer review interaction","group":{"name":"peer_review_taxonomy"}},{"value":"review summaries, review reports, author\/editor communication, reviewer identities reviewer opt in, editor identities","name":"peer_review_published","label":"Peer review published","group":{"name":"peer_review_taxonomy"}},{"value":"open (sign in with ORCID iD required)","name":"post_publication_commenting","label":"Post publication commenting","group":{"name":"post_publication_commenting"}}],"article-number":"e85773"}}