{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T17:04:59Z","timestamp":1790183099153,"version":"4.1.0"},"reference-count":52,"publisher":"National Academy of Sciences","issue":"39","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["NS107671"],"award-info":[{"award-number":["NS107671"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["R24-GM15042"],"award-info":[{"award-number":["R24-GM15042"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,9,29]]},"abstract":"<jats:p>Isoform-selective opening of voltage-gated potassium (Kv) channels is desirable for its therapeutic potential yet mechanistically little-understood. Rosemary leaf metabolite carnosic acid (CA) is a high-efficacy opener of the neuronal Kv7.3 channel but exerts minimal effects on Kv7.2 or Kv7.2\/3 heteromers. Here, using alanine-scanning mutagenesis, electrophysiology, radioligand binding, and all-atom molecular dynamics simulations, we found that CA achieves high-efficacy activation of Kv7.3 by binding at the extracellular cap of the voltage-sensing domain (VSD), independent of the canonical retigabine pore binding site. Kv7.3 samples a binding-competent VSD conformation absent in Kv7.2, characterized by an expanded extracellular pocket and a favorable electrostatic environment. Central to this mechanism, Kv7.3-L226 functions as a hydrophobic latch that tunes the energetic landscape of the voltage sensor to control ligand efficacy. Unexpectedly, CA potentiates Kv7.2\/3 activation by retigabine via ligand-initiated positive allosteric coupling between the VSD and pore, thus enhancing the anticonvulsant action of retigabine despite CA lacking standalone anticonvulsant activity. The findings establish a mechanistic framework in which isoform selectivity arises from VSD conformational microenvironments rather than canonical binding determinants and highlight the voltage sensor as a tunable target for developing selective Kv channel openers.<\/jats:p>","DOI":"10.1073\/pnas.2616367123","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T16:25:03Z","timestamp":1790180703000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Voltage-sensor conformational microenvironments encode isoform-selective ion channel activation"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0057-3541","authenticated-orcid":false,"given":"R\u00edan W.","family":"Manville","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04gyf1771","id-type":"ROR","asserted-by":"publisher"}],"name":"Bioelectricity Laboratory, Department of Physiology 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W. Manville Data from \u201cVoltage-sensor conformational microenvironments encode isoform-selective ion channel activation.\u201d Dryad. https:\/\/datadryad.org\/dataset\/doi:10.5061\/dryad.xsj3tx9xf. 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