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Pharmacol."],"abstract":"<jats:p>Venomous animals have evolved to produce peptide toxins that modulate the activity of voltage-gated sodium (Na<jats:sub>v<\/jats:sub>) channels. These specific modulators are powerful probes for investigating the structural and functional features of Na<jats:sub>v<\/jats:sub> channels. Here, we report the isolation and characterization of \u03b4-theraphotoxin-Gr4b (Gr4b), a novel peptide toxin from the venom of the spider <jats:italic>Grammostola rosea.<\/jats:italic> Gr4b contains 37-amino acid residues with six cysteines forming three disulfide bonds<jats:italic>.<\/jats:italic> Patch-clamp analysis confirmed that Gr4b markedly slows the fast inactivation of Na<jats:sub>v<\/jats:sub>1.9 and inhibits the currents of Na<jats:sub>v<\/jats:sub>1.4 and Na<jats:sub>v<\/jats:sub>1.7, but does not affect Na<jats:sub>v<\/jats:sub>1.8. It was also found that Gr4b significantly shifts the steady-state activation and inactivation curves of Na<jats:sub>v<\/jats:sub>1.9 to the depolarization direction and increases the window current, which is consistent with the change in the ramp current. Furthermore, analysis of Na<jats:sub>v<\/jats:sub>1.9\/Na<jats:sub>v<\/jats:sub>1.8 chimeric channels revealed that Gr4b preferentially binds to the voltage-sensor of domain III (DIII VSD) and has additional interactions with the DIV VSD. The site-directed mutagenesis analysis indicated that N1139 and L1143 in DIII S3-S4 linker participate in toxin binding. In sum, this study reports a novel spider peptide toxin that may slow the fast inactivation of Na<jats:sub>v<\/jats:sub>1.9 by binding to the new neurotoxin receptor site-DIII VSD. Taken together, these findings provide insight into the functional role of the Na<jats:sub>v<\/jats:sub> channel DIII VSD in fast inactivation and activation.<\/jats:p>","DOI":"10.3389\/fphar.2021.778534","type":"journal-article","created":{"date-parts":[[2021,12,6]],"date-time":"2021-12-06T06:31:23Z","timestamp":1638772283000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["A Novel Spider Toxin Inhibits Fast Inactivation of the Nav1.9 Channel by Binding to Domain III and Domain IV Voltage Sensors"],"prefix":"10.3389","volume":"12","author":[{"given":"Shuijiao","family":"Peng","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minzhi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhen","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sen","family":"Luo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Songping","family":"Liang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xi","family":"Zhou","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":[[2021,12,6]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"11844","DOI":"10.1021\/bi061111z","article-title":"Vstx1, a Modifier of Kv Channel Gating, Localizes to the Interfacial Region of Lipid Bilayers","volume":"45","author":"Bemporad","year":"2006","journal-title":"Biochemistry"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1079","DOI":"10.1152\/physrev.00052.2017","article-title":"The Role of Voltage-Gated Sodium Channels in Pain Signaling","volume":"99","author":"Bennett","year":"2019","journal-title":"Physiol. 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