{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:36:28Z","timestamp":1785404188418,"version":"3.56.0"},"reference-count":29,"publisher":"Rockefeller University Press","issue":"10","license":[{"start":{"date-parts":[[2023,8,1]],"date-time":"2023-08-01T00:00:00Z","timestamp":1690848000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.rupress.org\/terms\/"},{"start":{"date-parts":[[2024,1,30]],"date-time":"2024-01-30T00:00:00Z","timestamp":1706572800000},"content-version":"vor","delay-in-days":182,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01GM116961"],"award-info":[{"award-number":["R01GM116961"]}],"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":["R01HL131461"],"award-info":[{"award-number":["R01HL131461"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Pittsburgh Supercomputing Center"},{"DOI":"10.13039\/501100003748","name":"Swedish Society for Medical Research","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003748","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"publisher","award":["2017-02040"],"award-info":[{"award-number":["2017-02040"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["850622"],"award-info":[{"award-number":["850622"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,10,2]]},"abstract":"<jats:p>The KCNQ1 channel is important for the repolarization phase of the cardiac action potential. Loss of function mutations in KCNQ1 can cause long QT syndrome (LQTS), which can lead to cardiac arrythmia and even sudden cardiac death. We have previously shown that polyunsaturated fatty acids (PUFAs) and PUFA analogs can activate the cardiac KCNQ1 channel, making them potential therapeutics for the treatment of LQTS. PUFAs bind to KCNQ1 at two different binding sites: one at the voltage sensor (Site I) and one at the pore (Site II). PUFA interaction at Site I shifts the voltage dependence of the channel to the left, while interaction at Site II increases maximal conductance. The PUFA analogs, linoleic\u2013glycine and linoleic\u2013tyrosine, are more effective than linoleic acid at Site I, but less effective at Site II. Using both simulations and experiments, we find that the larger head groups of linoleic\u2013glycine and linoleic\u2013tyrosine interact with more residues than the smaller linoleic acid at Site I. We propose that this will stabilize the negatively charged PUFA head group in a position to better interact electrostatically with the positively charges in the voltage sensor. In contrast, the larger head groups of linoleic\u2013glycine and linoleic\u2013tyrosine compared with linoleic acid prevent a close fit of these PUFA analogs in Site II, which is more confined. In addition, we identify several KCNQ1 residues as critical PUFA-analog binding residues, thereby providing molecular models of specific interactions between PUFA analogs and KCNQ1. These interactions will aid in future drug development based on PUFA\u2013KCNQ1 channel interactions.<\/jats:p>","DOI":"10.1085\/jgp.202313339","type":"journal-article","created":{"date-parts":[[2023,7,19]],"date-time":"2023-07-19T02:20:51Z","timestamp":1689733251000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":15,"title":["Mechanistic understanding of KCNQ1 activating polyunsaturated fatty acid analogs"],"prefix":"10.1085","volume":"155","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6716-1787","authenticated-orcid":true,"given":"Jessica J.","family":"Jowais","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02dgjyy92","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Miami 1 Department of Physiology and Biophysics, , Miami, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2198-4590","authenticated-orcid":true,"given":"Samira","family":"Yazdi","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05ynxx418","id-type":"ROR","asserted-by":"publisher"}],"name":"Link\u00f6ping University 2 Department of Biomedical and Clinical Sciences, , Link\u00f6ping, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4556-9869","authenticated-orcid":true,"given":"Alessia","family":"Golluscio","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02dgjyy92","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Miami 1 Department of Physiology and Biophysics, , Miami, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3365-2365","authenticated-orcid":true,"given":"Vanessa","family":"Olivier-Meo","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02dgjyy92","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Miami 1 Department of Physiology and Biophysics, , Miami, FL, USA"}],"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":"Link\u00f6ping University 2 Department of Biomedical and Clinical Sciences, , Link\u00f6ping, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1688-2525","authenticated-orcid":true,"given":"H. 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