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In the pursuit of novel Na<jats:sub>V<\/jats:sub> modulators, we investigated spider venoms for new inhibitors of Na<jats:sub>V<\/jats:sub> channels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We used high\u2010throughput screens to identify a Na<jats:sub>V<\/jats:sub> modulator in venom of the spider <jats:italic>Davus fasciatus<\/jats:italic>. Further characterization of this venom peptide was undertaken using fluorescent and electrophysiological assays, molecular modelling and a rodent pain model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>We identified a potent Na<jats:sub>V<\/jats:sub> inhibitor named \u03bc\u2010TRTX\u2010Df1a. This 34\u2010residue peptide fully inhibited responses mediated by Na<jats:sub>V<\/jats:sub>1.7 endogenously expressed in SH\u2010SY5Y cells. Df1a also inhibited voltage\u2010gated calcium (Ca<jats:sub>V<\/jats:sub>3) currents but had no activity against the voltage\u2010gated potassium (K<jats:sub>V<\/jats:sub>2) channel. The modelled structure of Df1a, which contains an inhibitor cystine knot motif, is reminiscent of the Na<jats:sub>V<\/jats:sub> channel toxin ProTx\u2010I. Electrophysiology revealed that Df1a inhibits all Na<jats:sub>V<\/jats:sub> subtypes tested (hNa<jats:sub>V<\/jats:sub>1.1\u20131.7). Df1a also slowed fast inactivation of Na<jats:sub>V<\/jats:sub>1.1, Na<jats:sub>V<\/jats:sub>1.3 and Na<jats:sub>V<\/jats:sub>1.5 and modified the voltage\u2010dependence of activation and inactivation of most of the Na<jats:sub>V<\/jats:sub> subtypes. Df1a preferentially binds to the domain II voltage\u2010sensor and has additional interactions with the voltage sensors domains III and IV, which probably explains its modulatory features. Df1a was analgesic <jats:italic>in vivo,<\/jats:italic> reversing the spontaneous pain behaviours induced by the Na<jats:sub>V<\/jats:sub> activator OD1.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>\u03bc\u2010TRTX\u2010Df1a shows potential as a new molecule for the development of drugs to treat pain disorders mediated by voltage\u2010gated ion channels.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13865","type":"journal-article","created":{"date-parts":[[2017,5,25]],"date-time":"2017-05-25T16:42:41Z","timestamp":1495730561000},"page":"2528-2544","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Modulatory features of the novel spider toxin \u03bc\u2010TRTX\u2010Df1a isolated from the venom of the spider <i>Davus fasciatus<\/i>"],"prefix":"10.1111","volume":"174","author":[{"given":"Fernanda C","family":"Cardoso","sequence":"first","affiliation":[{"name":"Institute for Molecular Bioscience The University of Queensland  St Lucia QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zoltan","family":"Dekan","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience The University of Queensland  St Lucia QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer J","family":"Smith","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience The University of Queensland  St Lucia QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer R","family":"Deuis","sequence":"additional","affiliation":[{"name":"Institute for Molecular Bioscience The University of Queensland  St Lucia QLD Australia"},{"name":"School of Pharmacy The University of Queensland  Woolloongabba QLD Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina","family":"Vetter","sequence":"additional","affiliation":[{"name":"Institute for 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