{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T04:39:42Z","timestamp":1790224782829,"version":"4.1.0"},"reference-count":60,"publisher":"National Academy of Sciences","issue":"2","license":[{"start":{"date-parts":[[2024,12,30]],"date-time":"2024-12-30T00:00:00Z","timestamp":1735516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["GM130377"],"award-info":[{"award-number":["GM130377"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Susan Samueli Integrative Health Institute","award":["Samueli Scholarship"],"award-info":[{"award-number":["Samueli Scholarship"]}]},{"DOI":"10.13039\/100000060","name":"HHS | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI167034"],"award-info":[{"award-number":["AI167034"]}],"id":[{"id":"10.13039\/100000060","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":[[2025,1,14]]},"abstract":"<jats:p>\n                    Loss-of-function sequence variants in\n                    <jats:italic>KCNA1<\/jats:italic>\n                    , which encodes the voltage-gated potassium channel Kv1.1, cause Episodic Ataxia Type 1 (EA1) and epilepsy. Due to a paucity of drugs that directly rescue mutant Kv1.1 channel function, current therapeutic strategies for\n                    <jats:italic>KCNA1<\/jats:italic>\n                    -linked disorders involve indirect modulation of neuronal excitability. Native Americans have traditionally used conifer extracts to treat paralysis, weakness, and pain, all of which may involve altered electrical activity and\/or Kv1.1 dysfunction specifically. Here, screening conifer extracts, we found that\n                    <jats:italic>Chamaecyparis pisifera<\/jats:italic>\n                    increases wild-type (WT) Kv1.1 activity, as does its prominent metabolite, the abietane diterpenoid pisiferic acid. Uniquely, pisiferic acid also restored function in 12\/12 EA1-linked mutant Kv1.1 channels tested in vitro. Crucially, pisiferic acid (1 mg\/kg) restored WT function in Kv1.1\n                    <jats:sup>E283K\/+<\/jats:sup>\n                    mice, a model of human EA1. Experimentally validated all-atom molecular dynamics simulations in a neuron-like membrane revealed that the Kv1.1 voltage-sensing domain (VSD) also acts as a ligand-binding domain akin to those of classic ligand-gated channels; binding of pisiferic acid induces a conformational shift in the VSD that ligand-dependently opens the pore. Conifer metabolite pisiferic acid is a promising and versatile therapeutic lead for EA1 and other Kv1.1-linked disorders.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2411816122","type":"journal-article","created":{"date-parts":[[2024,12,30]],"date-time":"2024-12-30T15:01:44Z","timestamp":1735570904000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":7,"title":["A conifer metabolite corrects episodic ataxia type 1 by voltage sensor\u2013mediated ligand activation of Kv1.1"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0057-3541","authenticated-orcid":false,"given":"R\u00edan W.","family":"Manville","sequence":"first","affiliation":[{"name":"Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California","place":["Irvine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Foglia","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, School of Medicine, University of California","place":["Irvine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan F.","family":"Yoshimura","sequence":"additional","affiliation":[{"name":"Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California","place":["Irvine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7677-7882","authenticated-orcid":false,"given":"Derk J.","family":"Hogenkamp","sequence":"additional","affiliation":[{"name":"Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California","place":["Irvine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California","place":["Irvine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8051-7661","authenticated-orcid":false,"given":"Alvin","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biophysics, School of Medicine, University of California","place":["Irvine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4552-496X","authenticated-orcid":false,"given":"Geoffrey W.","family":"Abbott","sequence":"additional","affiliation":[{"name":"Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California","place":["Irvine"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,12,30]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1094-136"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.57.8.1499"},{"key":"e_1_3_4_3_2","volume-title":"GeneReviews((R))","author":"Hasan S. 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