{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T04:02:55Z","timestamp":1768449775088,"version":"3.49.0"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T00:00:00Z","timestamp":1623283200000},"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:p>The naturally occurred peptide toxins from animal venoms are valuable pharmacological tools in exploring the structure-function relationships of ion channels. Herein we have identified the peptide toxin \u03ba-LhTx-1 from the venom of spider <jats:italic>Pandercetes sp<\/jats:italic> (the Lichen huntsman spider) as a novel selective antagonist of the K<jats:sub>V<\/jats:sub>4 family potassium channels. \u03ba-LhTx-1 is a gating-modifier toxin impeded K<jats:sub>V<\/jats:sub>4 channels\u2019 voltage sensor activation, and mutation analysis has confirmed its binding site on channels\u2019 S3b region. Interestingly, \u03ba-LhTx-1 differently modulated the gating of K<jats:sub>V<\/jats:sub>4 channels, as revealed by toxin inhibiting K<jats:sub>V<\/jats:sub>4.2\/4.3 with much more stronger voltage-dependence than that for K<jats:sub>V<\/jats:sub>4.1. We proposed that \u03ba-LhTx-1 trapped the voltage sensor of K<jats:sub>V<\/jats:sub>4.1 in a much more stable resting state than that for K<jats:sub>V<\/jats:sub>4.2\/4.3 and further explored the underlying mechanism. Swapping the non-conserved S3b segments between K<jats:sub>V<\/jats:sub>4.1(<jats:sub>280<\/jats:sub>FVPK<jats:sub>283<\/jats:sub>) and K<jats:sub>V<\/jats:sub>4.3(<jats:sub>275<\/jats:sub>VMTN<jats:sub>278<\/jats:sub>) fully reversed their voltage-dependence phenotypes in inhibition by \u03ba-LhTx-1, and intensive mutation analysis has identified P282 in K<jats:sub>V<\/jats:sub>4.1, D281 in K<jats:sub>V<\/jats:sub>4.2 and N278 in K<jats:sub>V<\/jats:sub>4.3 being the key residues. Furthermore, the last two residues in this segment of each K<jats:sub>V<\/jats:sub>4 channel (P282\/K283 in K<jats:sub>V<\/jats:sub>4.1, T280\/D281 in K<jats:sub>V<\/jats:sub>4.2 and T277\/N278 in K<jats:sub>V<\/jats:sub>4.3) likely worked synergistically as revealed by our combinatorial mutations analysis. The present study has clarified the molecular basis in K<jats:sub>V<\/jats:sub>4 channels for their different modulations by \u03ba-LhTx-1, which have advanced our understanding on K<jats:sub>V<\/jats:sub>4 channels\u2019 structure features. Moreover, \u03ba-LhTx-1 might be useful in developing anti-arrhythmic drugs given its high affinity, high selectivity and unique action mode in interacting with the K<jats:sub>V<\/jats:sub>4.2\/4.3 channels.<\/jats:p>","DOI":"10.3389\/fphar.2021.692076","type":"journal-article","created":{"date-parts":[[2021,6,10]],"date-time":"2021-06-10T08:54:30Z","timestamp":1623315270000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Variation of Two S3b Residues in KV4.1\u20134.3 Channels Underlies Their Different Modulations by Spider Toxin \u03ba-LhTx-1"],"prefix":"10.3389","volume":"12","author":[{"given":"Zhen","family":"Xiao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Piao","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangyue","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangjin","family":"Kong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruiwen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Songping","family":"Liang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhonghua","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2021,6,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1038\/35000592","article-title":"Modulation of A-type Potassium Channels by a Family of Calcium Sensors","volume":"403","author":"An","year":"2000","journal-title":"Nature"},{"key":"B2","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1093\/europace\/euw235","article-title":"J-Wave Syndromes Expert Consensus Conference Report: Emerging Concepts and Gaps in Knowledge","volume":"19","author":"Antzelevitch","year":"2017","journal-title":"Europace"},{"key":"B3","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.cpcardiol.2015.06.002","article-title":"Brugada Syndrome: Clinical, Genetic, Molecular, Cellular, and Ionic Aspects","volume":"41","author":"Antzelevitch","year":"2016","journal-title":"Curr. 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