{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T19:02:48Z","timestamp":1782586968565,"version":"3.54.5"},"reference-count":72,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,5,19]],"date-time":"2022-05-19T00:00:00Z","timestamp":1652918400000},"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>Voltage-gated sodium channel Na<jats:sub>V<\/jats:sub>1.8 regulates transmission of pain signals to the brain. While Na<jats:sub>V<\/jats:sub>1.8 has the potential to serve as a drug target, the molecular mechanisms that shape Na<jats:sub>V<\/jats:sub>1.8 gating are not completely understood, particularly mechanisms that couple activation to inactivation. Interactions between toxin producing animals and their predators provide a novel approach for investigating Na<jats:sub>V<\/jats:sub> structure-function relationships. Arizona bark scorpions produce Na<jats:sup>+<\/jats:sup> channel toxins that initiate pain signaling. However, in predatory grasshopper mice, toxins inhibit Na<jats:sub>V<\/jats:sub>1.8 currents and block pain signals. A screen of synthetic peptide toxins predicted from bark scorpion venom showed that peptide NaTx36 inhibited Na<jats:sup>+<\/jats:sup> current recorded from a recombinant grasshopper mouse Na<jats:sub>V<\/jats:sub>1.8 channel (OtNa<jats:sub>V<\/jats:sub>1.8). Toxin NaTx36 hyperpolarized OtNa<jats:sub>V<\/jats:sub>1.8 activation, steady-state fast inactivation, and slow inactivation. Mutagenesis revealed that the first gating charge in the domain I (DI) S4 voltage sensor and an acidic amino acid (E) in the DII SS2 \u2013 S6 pore loop are critical for the inhibitory effects of NaTx36. Computational modeling showed that a DI S1 \u2013 S2 asparagine (N) stabilizes the NaTx36 \u2013 OtNa<jats:sub>V<\/jats:sub>1.8 complex while residues in the DI S3 \u2013 S4 linker and S4 voltage sensor form electrostatic interactions that allow a toxin glutamine (Q) to contact the first S4 gating charge. Surprisingly, the models predicted that NaTx36 contacts amino acids in the DII S5 \u2013 SS1 pore loop instead of the SS2 \u2013 S6 loop; the DII SS2 \u2013 S6 loop motif (QVSE) alters the conformation of the DII S5 \u2013 SS1 pore loop, enhancing allosteric interactions between toxin and the DII S5 \u2013 SS1 pore loop. Few toxins have been identified that modify Na<jats:sub>V<\/jats:sub>1.8 gating. Moreover, few toxins have been described that modify sodium channel gating via the DI S4 voltage sensor. Thus, NaTx36 and OtNa<jats:sub>V<\/jats:sub>1.8 provide tools for investigating the structure-activity relationship between channel activation and inactivation gating, and the connection to alternative pain phenotypes.<\/jats:p>","DOI":"10.3389\/fphar.2022.846992","type":"journal-article","created":{"date-parts":[[2022,5,19]],"date-time":"2022-05-19T05:59:42Z","timestamp":1652939982000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Structural and Functional Characterization of a Novel Scorpion Toxin that Inhibits NaV1.8 via Interactions With the DI Voltage Sensor and DII Pore Module"],"prefix":"10.3389","volume":"13","author":[{"given":"Kiran","family":"George","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Lopez-Mateos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tarek Mohamed","family":"Abd El-Aziz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yucheng","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jake","family":"Kline","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Bao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Syed","family":"Raza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James D.","family":"Stockand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodore R.","family":"Cummins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Fornelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew P.","family":"Rowe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir","family":"Yarov-Yarovoy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashlee H.","family":"Rowe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,5,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1085\/jgp.201511492","article-title":"The Hitchhiker's Guide to the Voltage-Gated Sodium Channel Galaxy","volume":"147","author":"Ahern","year":"2016","journal-title":"J. Gen. Physiol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"3031","DOI":"10.1021\/acs.jctc.7b00125","article-title":"The Rosetta All-Atom Energy Function for Macromolecular Modeling and Design","volume":"13","author":"Alford","year":"2017","journal-title":"J. Chem. Theor. Comput"},{"key":"B3","doi-asserted-by":"publisher","first-page":"17991","DOI":"10.1073\/pnas.0607603103","article-title":"Na Channel Inactivation from Open and Closed States","volume":"103","author":"Armstrong","year":"2006","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B4","doi-asserted-by":"publisher","first-page":"871","DOI":"10.1126\/science.abj8754","article-title":"Accurate Prediction of Protein Structures and Interactions Using a Three-Track Neural Network","volume":"373","author":"Baek","year":"2021","journal-title":"Science"},{"key":"B5","first-page":"599","article-title":"Unusual Voltage-Gated Sodium Currents as Targets for Pain","volume-title":"Current Topics in Membranes","author":"Barbosa","year":"2016"},{"key":"B6","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1016\/j.cell.2009.09.028","article-title":"Cellular and Molecular Mechanisms of Pain","volume":"139","author":"Basbaum","year":"2009","journal-title":"Cell"},{"key":"B7","doi-asserted-by":"publisher","first-page":"10338","DOI":"10.1523\/jneurosci.23-32-10338.2003","article-title":"Role of Tetrodotoxin-Resistant Na+ Current Slow Inactivation in Adaptation of Action Potential Firing in Small-Diameter Dorsal Root Ganglion Neurons","volume":"23","author":"Blair","year":"2003","journal-title":"J. Neurosci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"10277","DOI":"10.1523\/jneurosci.22-23-10277.2002","article-title":"Roles of Tetrodotoxin (TTX)-Sensitive Na+ Current, TTX-Resistant Na+ Current, and Ca2+ Current in the Action Potentials of Nociceptive Sensory Neurons","volume":"22","author":"Blair","year":"2002","journal-title":"J. Neurosci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1016\/j.tips.2009.12.007","article-title":"Targeting Voltage Sensors in Sodium Channels with Spider Toxins","volume":"31","author":"Bosmans","year":"2010","journal-title":"Trends Pharmacol. Sci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1016\/j.toxicon.2006.09.023","article-title":"Voltage-gated Sodium Channel Modulation by Scorpion Alpha-Toxins","volume":"49","author":"Bosmans","year":"2007","journal-title":"Toxicon"},{"key":"B11","doi-asserted-by":"publisher","first-page":"2090","DOI":"10.1056\/NEJMoa0808455","article-title":"Antivenom for Critically Ill Children with Neurotoxicity from Scorpion Stings","volume":"360","author":"Boyer","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"B12","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1085\/jgp.200809995","article-title":"Alpha-scorpion Toxin Impairs a Conformational Change that Leads to Fast Inactivation of Muscle Sodium Channels","volume":"132","author":"Campos","year":"2008","journal-title":"J. Gen. Physiol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.abb.2017.12.012","article-title":"Intraspecific Variation of Centruroides Sculpturatus Scorpion Venom from Two Regions of Arizona","volume":"638","author":"Carcamo-Noriega","year":"2018","journal-title":"Arch. Biochem. Biophys."},{"key":"B14","doi-asserted-by":"publisher","first-page":"S15","DOI":"10.1152\/physrev.1992.72.suppl_4.S15","article-title":"Cellular and Molecular Biology of Voltage-Gated Sodium Channels","volume":"72","author":"Catterall","year":"1992","journal-title":"Physiol. Rev."},{"key":"B15","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.toxicon.2006.09.022","article-title":"Voltage-gated Ion Channels and Gating Modifier Toxins","volume":"49","author":"Catterall","year":"2007","journal-title":"Toxicon"},{"key":"B16","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/s0896-6273(00)81133-2","article-title":"From Ionic Currents to Molecular Mechanisms: the Structure and Function of Voltage-Gated Sodium Channels","volume":"26","author":"Catterall","year":"2000","journal-title":"Neuron"},{"key":"B17","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1124\/pr.57.4.4","article-title":"International Union of Pharmacology. XLVII. Nomenclature and Structure-Function Relationships of Voltage-Gated Sodium Channels","volume":"57","author":"Catterall","year":"2005","journal-title":"Pharmacol. Rev."},{"key":"B18","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1146\/annurev.pa.20.040180.000311","article-title":"Neurotoxins that Act on Voltage-Sensitive Sodium Channels in Excitable Membranes","volume":"20","author":"Catterall","year":"1980","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1113\/expphysiol.2013.071969","article-title":"Structure and Function of Voltage-Gated Sodium Channels at Atomic Resolution","volume":"99","author":"Catterall","year":"2014","journal-title":"Exp. Physiol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"9075","DOI":"10.1073\/pnas.0901507106","article-title":"Distinct Subsets of Unmyelinated Primary Sensory Fibers Mediate Behavioral Responses to Noxious thermal and Mechanical Stimuli","volume":"106","author":"Cavanaugh","year":"2009","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B21","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1016\/s0300-9084(00)01174-3","article-title":"Molecular Mechanisms of Neurotoxin Action on Voltage-Gated Sodium Channels","volume":"82","author":"Cest\u00e8le","year":"2000","journal-title":"Biochimie"},{"key":"B22","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1016\/s0896-6273(00)80606-6","article-title":"Voltage Sensor-Trapping: Enhanced Activation of Sodium Channels by Beta-Scorpion Toxin Bound to the S3-S4 Loop in Domain II","volume":"21","author":"Cest\u00e8le","year":"1998","journal-title":"Neuron"},{"key":"B23","doi-asserted-by":"publisher","first-page":"1333","DOI":"10.1085\/jgp.201812118","article-title":"The Voltage-Gated Sodium Channel Pore Exhibits Conformational Flexibility during Slow Inactivation","volume":"150","author":"Chatterjee","year":"2018","journal-title":"J. Gen. Physiol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"eaav8573","DOI":"10.1126\/science.aav8573","article-title":"Structural Basis of \u03b1-scorpion Toxin Action on Nav Channels","volume":"363","author":"Clairfeuille","year":"2019","journal-title":"Science"},{"key":"B25","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1002\/pro.2389","article-title":"Relaxation of Backbone Bond Geometry Improves Protein Energy Landscape Modeling","volume":"23","author":"Conway","year":"2014","journal-title":"Protein Sci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"1893","DOI":"10.1016\/s0041-0101(01)00174-x","article-title":"Genes and Peptides from the Scorpion Centruroides Sculpturatus Ewing, that Recognize Na(+)-Channels","volume":"39","author":"Corona","year":"2001","journal-title":"Toxicon"},{"key":"B27","first-page":"659","article-title":"Mechanism of Action of Scorpion Toxins","volume-title":"Handbook of Natural Toxins","author":"Couraud","year":"1984"},{"key":"B28","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1016\/j.pain.2007.07.026","article-title":"The Roles of Sodium Channels in Nociception: Implications for Mechanisms of Pain","volume":"131","author":"Cummins","year":"2007","journal-title":"Pain"},{"key":"B29","doi-asserted-by":"publisher","first-page":"3503","DOI":"10.1523\/jneurosci.17-10-03503.1997","article-title":"Downregulation of Tetrodotoxin-Resistant Sodium Currents and Upregulation of a Rapidly Repriming Tetrodotoxin-Sensitive Sodium Current in Small Spinal Sensory Neurons after Nerve Injury","volume":"17","author":"Cummins","year":"1997","journal-title":"J. Neurosci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"417","DOI":"10.3109\/15563658308990433","article-title":"Envenomation by the Scorpion Centruroides Sculpturatus","volume":"21","author":"Curry","year":"1983","journal-title":"J. Toxicol. Clin. Toxicol."},{"key":"B31","doi-asserted-by":"publisher","first-page":"789570","DOI":"10.3389\/fphar.2021.789570","article-title":"The Tarantula Venom Peptide Eo1a Binds to the Domain II S3-S4 Extracellular Loop of Voltage-Gated Sodium Channel NaV1.8 to Enhance Activation","volume":"12","author":"Deuis","year":"2021","journal-title":"Front. Pharmacol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1146\/annurev-neuro-060909-153234","article-title":"Sodium Channels in normal and Pathological Pain","volume":"33","author":"Dib-Hajj","year":"2010","journal-title":"Annu. Rev. Neurosci."},{"key":"B33","doi-asserted-by":"publisher","first-page":"e2110932119","DOI":"10.1073\/pnas.2110932119","article-title":"Multitarget Nociceptor Sensitization by a Promiscuous Peptide from the Venom of the King Baboon Spider","volume":"119","author":"Finol-Urdaneta","year":"2022","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B34","first-page":"409","article-title":"Mechanism of Inactivation in Voltage-Gated Na+ Channels","volume-title":"Current Topics in Membranes","author":"Gawali","year":"2016"},{"key":"B35","first-page":"479","article-title":"Physiology and Pathophysiology of Sodium Channel Inactivation","volume-title":"Current Topics in Membranes","author":"Ghovanloo","year":"2016"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1863","DOI":"10.1113\/JP275102","article-title":"Using Voltage-Sensor Toxins and Their Molecular Targets to Investigate NaV 1.8 Gating","volume":"596","author":"Gilchrist","year":"2018","journal-title":"J. Physiol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1002\/pro.3235","article-title":"UCSF ChimeraX: Meeting Modern Challenges in Visualization and Analysis","volume":"27","author":"Goddard","year":"2018","journal-title":"Protein Sci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"3896","DOI":"10.1073\/pnas.79.12.3896","article-title":"Centruroides Toxin, a Selective Blocker of Surface Na+ Channels in Skeletal Muscle: Voltage-Clamp Analysis and Biochemical Characterization of the Receptor","volume":"79","author":"Jaimovich","year":"1982","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"B39","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1038\/s41467-020-20078-3","article-title":"Structural Basis for Voltage-Sensor Trapping of the Cardiac Sodium Channel by a Deathstalker Scorpion Toxin","volume":"12","author":"Jiang","year":"2021","journal-title":"Nat. Commun."},{"key":"B40","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly Accurate Protein Structure Prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"B41","doi-asserted-by":"publisher","first-page":"21","DOI":"10.3389\/fnana.2014.00021","article-title":"The Functional and Anatomical Dissection of Somatosensory Subpopulations Using Mouse Genetics","volume":"8","author":"Le Pichon","year":"2014","journal-title":"Front. Neuroanat."},{"key":"B42","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1113\/jphysiol.2005.093484","article-title":"Beta-scorpion Toxin Effects Suggest Electrostatic Interactions in Domain II of Voltage-dependent Sodium Channels","volume":"568","author":"Mantegazza","year":"2005","journal-title":"J. Physiol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"3461","DOI":"10.1093\/bioinformatics\/bty355","article-title":"Efficient Flexible Backbone Protein-Protein Docking for Challenging Targets","volume":"34","author":"Marze","year":"2018","journal-title":"Bioinformatics"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1101\/2021.08.15.456425","article-title":"ColabFold - Making Protein Folding Accessible to All","author":"Mirdita","year":"2021","journal-title":"bioRxiv"},{"key":"B45","doi-asserted-by":"publisher","first-page":"501","DOI":"10.3390\/toxins13070501","article-title":"Identification and Characterization of Novel Proteins from Arizona Bark Scorpion Venom that Inhibit Nav1.8, a Voltage-Gated Sodium Channel Regulator of Pain Signaling","volume":"13","author":"Mohamed Abd El-Aziz","year":"2021","journal-title":"Toxins"},{"key":"B46","doi-asserted-by":"publisher","first-page":"842032","DOI":"10.3389\/fphar.2022.842032","article-title":"Towards Structure-Guided Development of Pain Therapeutics Targeting Voltage-Gated Sodium Channels","volume":"13","author":"Nguyen","year":"2022","journal-title":"Front. Pharmacol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"260","DOI":"10.3390\/toxins12040260","article-title":"Defensive Venoms: Is Pain Sufficient for Predator Deterrence?","volume":"12","author":"Niermann","year":"2020","journal-title":"Toxins (Basel)"},{"key":"B48","doi-asserted-by":"publisher","first-page":"6836","DOI":"10.1073\/pnas.1621263114","article-title":"Pharmacology of the Nav1.1 Domain IV Voltage Sensor Reveals Coupling between Inactivation Gating Processes","volume":"114","author":"Osteen","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B49","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1126\/science.aaf8933","article-title":"Neural Circuits for Pain: Recent Advances and Current Views","volume":"354","author":"Peirs","year":"2016","journal-title":"Science"},{"key":"B50","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1046\/j.1432-1327.1999.00625.x","article-title":"Scorpion Toxins Specific for Na+-Channels","volume":"264","author":"Possani","year":"1999","journal-title":"Eur. J. Biochem."},{"key":"B51","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1016\/s0300-9084(00)01167-6","article-title":"Peptides and Genes Coding for Scorpion Toxins that Affect Ion-Channels","volume":"82","author":"Possani","year":"2000","journal-title":"Biochimie"},{"key":"B52","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1016\/s0896-6273(00)80606-6","article-title":"Voltage Sensor-Trapping","volume":"21","author":"Qu","year":"1998","journal-title":"Neuron"},{"key":"B53","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1152\/jn.2001.86.2.629","article-title":"Contribution of Na(v)1.8 Sodium Channels to Action Potential Electrogenesis in DRG Neurons","volume":"86","author":"Renganathan","year":"2001","journal-title":"J. Neurophysiol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1016\/j.toxicon.2004.03.022","article-title":"Current Views on Scorpion Toxins Specific for K+-channels","volume":"43","author":"Rodr\u00edguez de la Vega","year":"2004","journal-title":"Toxicon"},{"key":"B55","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1016\/j.toxicon.2005.09.006","article-title":"Overview of Scorpion Toxins Specific for Na+ Channels and Related Peptides: Biodiversity, Structure-Function Relationships and Evolution","volume":"46","author":"Rodr\u00edguez de la Vega","year":"2005","journal-title":"Toxicon"},{"key":"B56","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1016\/j.toxicon.2008.07.004","article-title":"Physiological Resistance of Grasshopper Mice (Onychomys spp.) to Arizona Bark Scorpion (Centruroides Exilicauda) Venom","volume":"52","author":"Rowe","year":"2008","journal-title":"Toxicon"},{"key":"B57","doi-asserted-by":"publisher","first-page":"441","DOI":"10.1126\/science.1236451","article-title":"Voltage-gated Sodium Channel in Grasshopper Mice Defends against Bark Scorpion Toxin","volume":"342","author":"Rowe","year":"2013","journal-title":"Science"},{"key":"B58","doi-asserted-by":"publisher","first-page":"e23520","DOI":"10.1371\/journal.pone.0023520","article-title":"Isolation and Characterization of CvIV4: a Pain Inducing \u03b1-scorpion Toxin","volume":"6","author":"Rowe","year":"2011","journal-title":"PLoS One"},{"key":"B59","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1016\/j.anbehav.2005.08.003","article-title":"Risk Assessment by Grasshopper Mice (Onychomys spp.) Feeding on Neurotoxic Prey (Centruroides spp.)","volume":"71","author":"Rowe","year":"2006","journal-title":"Anim. Behav."},{"key":"B60","doi-asserted-by":"publisher","first-page":"W331","DOI":"10.1093\/nar\/gkz368","article-title":"Protein Interaction Z Score Assessment (PIZSA): an Empirical Scoring Scheme for Evaluation of Protein-Protein Interactions","volume":"47","author":"Roy","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"B61","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1007\/978-3-642-41588-3_3","article-title":"Slow Inactivation of Na(+) Channels","volume":"221","author":"Silva","year":"2014","journal-title":"Handb Exp. Pharmacol."},{"key":"B62","first-page":"236","article-title":"Toxicolgy, Chemistry and Safety","volume-title":"Natural Toxins","author":"Simard","year":"1992"},{"key":"B63","doi-asserted-by":"publisher","first-page":"19980","DOI":"10.1073\/pnas.0810562105","article-title":"Depolarization-activated Gating Pore Current Conducted by Mutant Sodium Channels in Potassium-Sensitive Normokalemic Periodic Paralysis","volume":"105","author":"Sokolov","year":"2008","journal-title":"Proc. Natl. Acad. Sci. U S A."},{"key":"B64","doi-asserted-by":"publisher","first-page":"1271","DOI":"10.1152\/physrev.00024.2004","article-title":"Sodium Channel Inactivation: Molecular Determinants and Modulation","volume":"85","author":"Ulbricht","year":"2005","journal-title":"Physiol. Rev."},{"key":"B65","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1016\/j.toxicon.2010.06.008","article-title":"Isolation and Characterization of Two Novel Scorpion Toxins: The Alpha-toxin-like CeII8, Specific for Na(v)1.7 Channels and the Classical Anti-mammalian CeII9, Specific for Na(v)1.4 Channels","volume":"56","author":"Vandendriessche","year":"2010","journal-title":"Toxicon"},{"key":"B66","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1385\/CBB:35:2:171","article-title":"Slow Inactivation in Voltage-Gated Sodium Channels: Molecular Substrates and Contributions to Channelopathies","volume":"35","author":"Vilin","year":"2001","journal-title":"Cell Biochem Biophys"},{"key":"B67","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1124\/mol.114.092338","article-title":"Gating-Pore Currents Demonstrate Selective and Specific Modulation of Individual Sodium Channel Voltage-Sensors by Biological Toxins","volume":"86","author":"Xiao","year":"2014","journal-title":"Mol. Pharmacol."},{"key":"B68","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1007\/s13238-015-0154-4","article-title":"Scorpion Toxin BmK I Directly Activates Nav1.8 in Primary Sensory Neurons to Induce Neuronal Hyperexcitability in Rats","volume":"6","author":"Ye","year":"2015","journal-title":"Protein Cell"},{"key":"B69","doi-asserted-by":"publisher","first-page":"7324","DOI":"10.1074\/jbc.RA118.007370","article-title":"Naja Atra Venom Peptide Reduces Pain by Selectively Blocking the Voltage-Gated Sodium Channel Nav1.8","volume":"294","author":"Zhang","year":"2019","journal-title":"J. Biol. Chem."},{"key":"B70","doi-asserted-by":"publisher","first-page":"6371","DOI":"10.1523\/JNEUROSCI.3216-20.2021","article-title":"Cannabidiol Inhibition of Murine Primary Nociceptors: Tight Binding to Slow Inactivated States of Nav1.8 Channels","volume":"41","author":"Zhang","year":"2021","journal-title":"J. Neurosci."},{"key":"B71","doi-asserted-by":"publisher","first-page":"30719","DOI":"10.1074\/jbc.m112.370742","article-title":"Mapping the Interaction Site for a \u03b2-Scorpion Toxin in the Pore Module of Domain III of Voltage-Gated Na+ Channels","volume":"287","author":"Zhang","year":"2012","journal-title":"J. Biol. Chem."},{"key":"B72","doi-asserted-by":"publisher","first-page":"33641","DOI":"10.1074\/jbc.m111.282509","article-title":"Structure-Function Map of the Receptor Site for \u03b2-Scorpion Toxins in Domain II of Voltage-Gated Sodium Channels","volume":"286","author":"Zhang","year":"2011","journal-title":"J. Biol. Chem."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.846992\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,5,19]],"date-time":"2022-05-19T05:59:53Z","timestamp":1652939993000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.846992\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,19]]},"references-count":72,"alternative-id":["10.3389\/fphar.2022.846992"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.846992","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,19]]},"article-number":"846992"}}