{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T06:41:06Z","timestamp":1789713666884,"version":"4.0.1"},"reference-count":68,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,4,20]],"date-time":"2017-04-20T00:00:00Z","timestamp":1492646400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,4,20]],"date-time":"2017-04-20T00:00:00Z","timestamp":1492646400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Voltage-gated sodium (Na<jats:sub>V<\/jats:sub>) channels are essential for the transmission of pain signals in humans making them prime targets for the development of new analgesics. Spider venoms are a rich source of peptide modulators useful to study ion channel structure and function. Here we describe \u03b2\/\u03b4-TRTX-Pre1a, a 35-residue tarantula peptide that selectively interacts with neuronal Na<jats:sub>V<\/jats:sub> channels inhibiting peak current of hNa<jats:sub>V<\/jats:sub>1.1, rNa<jats:sub>V<\/jats:sub>1.2, hNa<jats:sub>V<\/jats:sub>1.6, and hNa<jats:sub>V<\/jats:sub>1.7 while concurrently inhibiting fast inactivation of hNa<jats:sub>V<\/jats:sub>1.1 and rNa<jats:sub>V<\/jats:sub>1.3. The DII and DIV S3-S4 loops of Na<jats:sub>V<\/jats:sub> channel voltage sensors are important for the interaction of Pre1a with Na<jats:sub>V<\/jats:sub> channels but cannot account for its unique subtype selectivity. Through analysis of the binding regions we ascertained that the variability of the S1-S2 loops between Na<jats:sub>V<\/jats:sub> channels contributes substantially to the selectivity profile observed for Pre1a, particularly with regards to fast inactivation. A serine residue on the DIV S2 helix was found to be sufficient to explain Pre1a\u2019s potent and selective inhibitory effect on the fast inactivation process of Na<jats:sub>V<\/jats:sub>1.1 and 1.3. This work highlights that interactions with both S1-S2 <jats:italic>and<\/jats:italic> S3-S4 of Na<jats:sub>V<\/jats:sub> channels may be necessary for functional modulation, and that targeting the diverse S1-S2 region within voltage-sensing domains provides an avenue to develop subtype selective tools.<\/jats:p>","DOI":"10.1038\/s41598-017-01129-0","type":"journal-article","created":{"date-parts":[[2017,4,11]],"date-time":"2017-04-11T17:26:16Z","timestamp":1491931576000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["The tarantula toxin \u03b2\/\u03b4-TRTX-Pre1a highlights the importance of the S1-S2 voltage-sensor region for sodium channel subtype selectivity"],"prefix":"10.1038","volume":"7","author":[{"given":"Joshua S.","family":"Wingerd","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine A.","family":"Mozar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine A.","family":"Ussing","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swetha S.","family":"Murali","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanni K.-Y.","family":"Chin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben","family":"Cristofori-Armstrong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Durek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Gilchrist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4314-7689","authenticated-orcid":false,"given":"Christopher W.","family":"Vaughan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Bosmans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7030-2288","authenticated-orcid":false,"given":"David J.","family":"Adams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Lewis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul F.","family":"Alewood","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2420-4262","authenticated-orcid":false,"given":"Mehdi","family":"Mobli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0622-609X","authenticated-orcid":false,"given":"Macdonald J.","family":"Christie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3616-0279","authenticated-orcid":false,"given":"Lachlan D.","family":"Rash","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,4,20]]},"reference":[{"key":"1129_CR1","unstructured":"Catterall, W. 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