{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T17:23:33Z","timestamp":1786123413981,"version":"build-2736575974"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Voltage-gated potassium channels of the K\n                      <jats:sub>V<\/jats:sub>\n                      3 subfamily, particularly K\n                      <jats:sub>V<\/jats:sub>\n                      3.1 (encoded by KCNC1), are essential regulators of fast-spiking inhibitory interneuron activity and high-frequency neuronal firing, enabling precise control of neuronal excitability and network synchrony. Growing evidence links K\n                      <jats:sub>V<\/jats:sub>\n                      3.1 dysfunction to epilepsy, schizophrenia, tinnitus, fragile X syndrome, amyotrophic lateral sclerosis, and KCNC1 related developmental and epileptic encephalopathies, positioning this channel as a promising therapeutic target.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This systematic review, conducted in accordance with PRISMA guidelines, evaluates original studies published between 2016 and January 2026 that investigated pharmacological modulation of K\n                      <jats:sub>V<\/jats:sub>\n                      3.1 using\n                      <jats:italic>in vitro<\/jats:italic>\n                      ,\n                      <jats:italic>in vivo<\/jats:italic>\n                      , structural, and translational approaches.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>A total of thirty-two studies met the predefined PICOS criteria. The literature reveals two pharmacological strategies: positive allosteric modulation aimed at enhancing fast-spiking inhibitory interneuron function and restoring excitation inhibition balance, and state-dependent channel inhibition, particularly relevant for pathogenic gain of function KCNC1 variants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      While early positive allosteric modulators demonstrated proof of mechanism with limited clinical success, second-generation compounds exhibit improved translational potential, including evidence that they modulate functional brain networks in humans. In parallel, clinically approved antidepressants have been identified as open-channel blockers of K\n                      <jats:sub>V<\/jats:sub>\n                      3.1, enabling mutation-specific therapeutic repurposing.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Collectively, these findings highlight K\n                      <jats:sub>V<\/jats:sub>\n                      3.1 modulation as a context-dependent and increasingly precise pharmacological strategy for neurological and neurodevelopmental disorders\n                      <jats:bold>.<\/jats:bold>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1821275","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T09:55:46Z","timestamp":1785491746000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["KV3.1 channel modulation: a systematic review of pharmacological intervention strategies"],"prefix":"10.3389","volume":"17","author":[{"given":"Eider","family":"Nu\u00f1ez","sequence":"first","affiliation":[{"name":"Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV\/EHU)","place":["Leioa, Bizkaia, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arantza","family":"Muguruza-Montero","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV\/EHU)","place":["Leioa, Bizkaia, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ane","family":"Arrizabalaga-Iriondo","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV\/EHU)","place":["Leioa, Bizkaia, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julian","family":"Zayas-Arrabal","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV\/EHU)","place":["Leioa, Bizkaia, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"M-Alicante","sequence":"additional","affiliation":[{"name":"Instituto Biofisika CSIC\u2013EHU","place":["Leioa, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janire","family":"Urrutia","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV\/EHU)","place":["Leioa, Bizkaia, Spain"]},{"name":"Biobizkaia Health Research Institute, Pediatric Oncology","place":["Barakaldo, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miren","family":"Revuelta","sequence":"additional","affiliation":[{"name":"Department of Physiology, Faculty of Medicine and Nursing, University of the Basque Country (UPV\/EHU)","place":["Leioa, Bizkaia, Spain"]},{"name":"Biobizkaia Health Research Institute, Otolaryngology and Language and Communication Disorders","place":["Barakaldo, Spain"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e148","DOI":"10.1111\/epi.17656","article-title":"A novel KCNC1 gain\u2010of\u2010function variant causing developmental and epileptic encephalopathy: \u201cprecision medicine\u201d approach with fluoxetine","volume":"64","author":"Ambrosino","year":"2023","journal-title":"Epilepsia"},{"key":"B2","doi-asserted-by":"publisher","first-page":"117685","DOI":"10.1016\/j.taap.2025.117685","article-title":"Duloxetine-induced inhibition of voltage-gated K+ 3.1 (kv3.1) channels and underlying electrophysiological mechanisms","volume":"507","author":"An","year":"2026","journal-title":"Toxicol. 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