{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T11:56:43Z","timestamp":1793707003110,"version":"4.6.1"},"reference-count":189,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T00:00:00Z","timestamp":1764633600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research","award":["23K06205"],"award-info":[{"award-number":["23K06205"]}]},{"name":"Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research","award":["23K27575"],"award-info":[{"award-number":["23K27575"]}]},{"name":"Sumitomo Foundation for Basic Science","award":["2300776"],"award-info":[{"award-number":["2300776"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Toxins as channel probes, small guanidinium alkaloids, such as tetrodotoxin and saxitoxin, canonical pore occlusion in voltage-gated Na+ channels. Cystine-rich peptides from spiders, scorpions, cone snails, and sea anemones, which act as pore blockers or gating modifiers targeting voltage-sensing domains. Recent structural and electrophysiological studies have identified specific binding sites on ion channels, including the S5\u2013S6 pore loops, outer vestibule and turret regions, and S3\u2013S4 \u201cpaddle\u201d motifs in NaV, Kv, and CaV channels. These discrete binding epitopes are recognized by different peptide toxins, enabling isoform- and state-specific modulation; for example, \u03bc-conotoxins bind the NaV pore, whereas charybdotoxin and agitoxin target the Kv outer vestibule. Beyond mechanistic insights, peptide toxins inspire translational strategies, including emerging therapies for retinal degenerative diseases. Photopharmacology using chemical photoswitches allows reversible, light-controlled modulation of ion channels in retinal ganglion cells without genetic manipulation or cell transplantation. Although BENAQ was discovered by small-molecule screening rather than toxin-guided design, its ion channel control demonstrates the potential of toxin-based molecular determinants for engineering synthetic compounds. This review thus integrates structural, functional, and translational perspectives, emphasizing the versatility of animal-derived peptide toxins as molecular probes and as blueprints for precision ion channel modulation in health and disease.<\/jats:p>","DOI":"10.3390\/toxins17120579","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T16:37:02Z","timestamp":1764952622000},"page":"579","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Ion Channel-Targeting Toxins: Structural Mechanisms of Activation, Inhibition, and Therapeutic Potential"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8326-6856","authenticated-orcid":false,"given":"Narumi","family":"Aoki-Shioi","sequence":"first","affiliation":[{"name":"Department of Medical Technology, Faculty of Fukuoka Medical Technology, Teikyo University, 6-22 Misakimachi, Omuta 836-8505, Fukuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-3467-6885","authenticated-orcid":false,"given":"Shuhei","family":"Nomura","sequence":"additional","affiliation":[{"name":"Department of Medical Technology, Faculty of Fukuoka Medical Technology, Teikyo University, 6-22 Misakimachi, Omuta 836-8505, Fukuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuyoshi","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, 19-1 8-chome, Nanakuma, Jonan-ku, Fukuoka 814-0180, Fukuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinichi","family":"Hirose","sequence":"additional","affiliation":[{"name":"General Medical Research Center School of Medicine, Fukuoka University, 45-1 7-chome Nanakuma Jonan-ku, Fukuoka 814-0180, Fukuoka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Felipe, A., and Ferrer-Montiel, A. 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