{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T20:08:19Z","timestamp":1790798899336,"version":"4.1.0"},"reference-count":89,"publisher":"National Academy of Sciences","issue":"31","license":[{"start":{"date-parts":[[2023,7,24]],"date-time":"2023-07-24T00:00:00Z","timestamp":1690156800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"HHS | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM131896"],"award-info":[{"award-number":["R35GM131896"]}],"id":[{"id":"10.13039\/100000057","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":[[2023,8]]},"abstract":"<jats:p>\n                    Loss-of-function mutations in the\n                    <jats:italic>KCNA1<\/jats:italic>\n                    (Kv1.1) gene cause episodic ataxia type 1 (EA1), a neurological disease characterized by cerebellar dysfunction, ataxic attacks, persistent myokymia with painful cramps in skeletal muscles, and epilepsy. Precision medicine for EA1 treatment is currently unfeasible, as no drug that can enhance the activity of Kv1.1-containing channels and offset the functional defects caused by\n                    <jats:italic>KCNA1<\/jats:italic>\n                    mutations has been clinically approved. Here, we uncovered that niflumic acid (NFA), a currently prescribed analgesic and anti-inflammatory drug with an excellent safety profile in the clinic, potentiates the activity of Kv1.1 channels. NFA increased Kv1.1 current amplitudes by enhancing the channel open probability, causing a hyperpolarizing shift in the voltage dependence of both channel opening and gating charge movement, slowing the OFF-gating current decay. NFA exerted similar actions on both homomeric Kv1.2 and heteromeric Kv1.1\/Kv1.2 channels, which are formed in most brain structures. We show that through its potentiating action, NFA mitigated the EA1 mutation\u2013induced functional defects in Kv1.1 and restored cerebellar synaptic transmission, Purkinje cell availability, and precision of firing. In addition, NFA ameliorated the motor performance of a\n                    <jats:italic>knock-in<\/jats:italic>\n                    mouse model of EA1 and restored the neuromuscular transmission and climbing ability in\n                    <jats:italic>Shaker<\/jats:italic>\n                    (Kv1.1) mutant\n                    <jats:italic>Drosophila melanogaster<\/jats:italic>\n                    flies (\n                    <jats:italic>\n                      Sh\n                      <jats:sup>5<\/jats:sup>\n                    <\/jats:italic>\n                    ). By virtue of its multiple actions, NFA has strong potential as an efficacious single-molecule-based therapeutic agent for EA1 and serves as a valuable model for drug discovery.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2207978120","type":"journal-article","created":{"date-parts":[[2023,7,24]],"date-time":"2023-07-24T15:08:10Z","timestamp":1690211290000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":25,"title":["An activator of voltage-gated K\n                    <sup>+<\/sup>\n                    channels Kv1.1 as a therapeutic candidate for episodic ataxia type 1"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6163-7975","authenticated-orcid":false,"given":"Ilenio","family":"Servettini","sequence":"first","affiliation":[{"name":"Section of Physiology, Department of Medicine, University of Perugia, Perugia 06123, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7642-557X","authenticated-orcid":false,"given":"Giuseppe","family":"Talani","sequence":"additional","affiliation":[{"name":"Institute of Neuroscience, National Research Council, Monserrato 09042, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3148-9568","authenticated-orcid":false,"given":"Alfredo","family":"Megaro","sequence":"additional","affiliation":[{"name":"Section of Physiology, Department of Medicine, University of Perugia, Perugia 06123, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6934-4042","authenticated-orcid":false,"given":"Maria Dolores","family":"Setzu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Cagliari, Monserrato 09042, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Biggio","sequence":"additional","affiliation":[{"name":"Department of Life and Environmental Sciences, University of Cagliari, Monserrato 09042, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1911-8709","authenticated-orcid":false,"given":"Michelle","family":"Briffa","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida MSD2080, Malta"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Guglielmi","sequence":"additional","affiliation":[{"name":"Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicoletta","family":"Savalli","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Perioperative Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Binda","sequence":"additional","affiliation":[{"name":"Department of Fundamental Neurosciences, University of Lausanne, Lausanne 1011, Switzerland"},{"name":"Centre National de la Recherche Scientifique, Institut des Neurosciences Cellulaires et Int\u00e9gratives, Universit\u00e9 de Strasbourg, Strasbourg F-67000, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis","family":"Delicata","sequence":"additional","affiliation":[{"name":"College of Pharmacy, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0T5, 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Pozzilli 86077, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6150-1608","authenticated-orcid":false,"given":"Ruben J.","family":"Cauchi","sequence":"additional","affiliation":[{"name":"Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, Msida MSD2080, Malta"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alba","family":"Di Pardo","sequence":"additional","affiliation":[{"name":"Istituto di Ricovero e Cura a Carattere Scientifico Neuromed, Pozzilli 86077, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Collu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Cagliari, Monserrato 09042, 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