{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T20:21:01Z","timestamp":1790713261360,"version":"4.1.0"},"reference-count":55,"publisher":"Rockefeller University Press","issue":"4","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,4,1]]},"abstract":"<jats:p>Scorpion \u03b2 toxins, peptides of \u223c70 residues, specifically target voltage-gated sodium (NaV) channels to cause use-dependent subthreshold channel openings via a voltage\u2013sensor trapping mechanism. This excitatory action is often overlaid by a not yet understood depressant mode in which NaV channel activity is inhibited. Here, we analyzed these two modes of gating modification by \u03b2-toxin Tz1 from Tityus zulianus on heterologously expressed NaV1.4 and NaV1.5 channels using the whole cell patch-clamp method. Tz1 facilitated the opening of NaV1.4 in a use-dependent manner and inhibited channel opening with a reversed use dependence. In contrast, the opening of NaV1.5 was exclusively inhibited without noticeable use dependence. Using chimeras of NaV1.4 and NaV1.5 channels, we demonstrated that gating modification by Tz1 depends on the specific structure of the voltage sensor in domain 2. Although residue G658 in NaV1.4 promotes the use-dependent transitions between Tz1 modification phenotypes, the equivalent residue in NaV1.5, N803, abolishes them. Gating charge neutralizations in the NaV1.4 domain 2 voltage sensor identified arginine residues at positions 663 and 669 as crucial for the outward and inward movement of this sensor, respectively. Our data support a model in which Tz1 can stabilize two conformations of the domain 2 voltage sensor: a preactivated outward position leading to NaV channels that open at subthreshold potentials, and a deactivated inward position preventing channels from opening. The results are best explained by a two-state voltage\u2013sensor trapping model in that bound scorpion \u03b2 toxin slows the activation as well as the deactivation kinetics of the voltage sensor in domain 2.<\/jats:p>","DOI":"10.1085\/jgp.201110720","type":"journal-article","created":{"date-parts":[[2012,3,26]],"date-time":"2012-03-26T16:49:46Z","timestamp":1332780586000},"page":"305-319","update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":50,"title":["Scorpion \u03b2-toxin interference with NaV channel voltage sensor gives rise to excitatory and depressant modes"],"prefix":"10.1085","volume":"139","author":[{"given":"Enrico","family":"Leipold","sequence":"first","affiliation":[{"name":"Department of Biophysics, Center for Molecular Biomedicine, Friedrich Schiller University of Jena and Jena University Hospital, Jena D-07745, Germany 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adolfo","family":"Borges","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda Molecular de Toxinas y Receptores, Instituto de Medicina Experimental, Universidad Central de Venezuela, Caracas 1050-A, Venezuela 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan H.","family":"Heinemann","sequence":"additional","affiliation":[{"name":"Department of Biophysics, Center for Molecular Biomedicine, Friedrich Schiller University of Jena and Jena University Hospital, Jena D-07745, Germany 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2012,3,26]]},"reference":[{"key":"2023072521395229900_bib1","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1016\/j.brainresbull.2007.03.007","article-title":"Suppression by intrathecal BmK IT2 on rat spontaneous pain behaviors and spinal c-Fos expression induced by formalin","volume":"73","author":"Bai","year":"2007","journal-title":"Brain Res. 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