ArticleMolecular pharmacology2010
The tarantula toxins ProTx-II and huwentoxin-IV differentially interact with human Nav1.7 voltage sensors to inhibit channel activation and inactivation.
Article in Molecular pharmacology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 76 papers.
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Who cites it
76 citing papers in PubMed, 137 citations in OpenAlex.
- Structural basis for inhibition of the voltage-gated sodium channel NaThe Journal of biological chemistry · 2026Article
- Refining the NaFEBS letters · 2025Article
- The venom ofFrontiers in pharmacology · 2025Article
- Harnessing Deep Learning Methods for Voltage-Gated Ion Channel Drug Discovery.Physiology (Bethesda, Md.) · 2025Review
- Optimizing Nav1.7-Targeted Analgesics: Revealing Off-Target Effects of Spider Venom-Derived Peptide Toxins and Engineering Strategies for Improvement.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Elucidating molecular mechanisms of protoxin-II state-specific binding to the human NaV1.7 channel.The Journal of general physiology · 2024Article
- Structure-function and rational design of a spider toxin Ssp1a at human voltage-gated sodium channel subtypes.Frontiers in pharmacology · 2023Article
- Differential expression of slow and fast-repriming tetrodotoxin-sensitive sodium currents in dorsal root ganglion neurons.Frontiers in molecular neuroscience · 2023Article
- Computational design of peptides to target NaeLife · 2022Article
- General mechanism of spider toxin family I acting on sodium channel Nav1.7.Zoological research · 2022Article
- Bioactive Peptides and Proteins from Centipede Venoms.Molecules (Basel, Switzerland) · 2022Review
- Non-canonical endogenous expression of voltage-gated sodium channel NaThe Journal of physiology · 2022Article
- Structural Advances in Voltage-Gated Sodium Channels.Frontiers in pharmacology · 2022Review
- Long March Toward Safe and Effective Analgesia by Enhancing Gene Expression ofFrontiers in molecular neuroscience · 2022Review
- Sodium Channels and Local Anesthetics-Old Friends With New Perspectives.Frontiers in pharmacology · 2022Review
- Selective Targeting of Nav1.7 with Engineered Spider Venom-Based Peptides.Channels (Austin, Tex.) · 2021Review
- Evaluation of Efficient Non-reducing Enzymatic and Chemical Ligation Strategies for Complex Disulfide-Rich Peptides.Bioconjugate chemistry · 2021Article
- Expression, Purification and Refolding of a Human NaToxins · 2021Article
- Article
- Interactions of Sea Anemone Toxins with Insect Sodium Channel-Insights from Electrophysiology and Molecular Docking Studies.Molecules (Basel, Switzerland) · 2021Article
16 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
Abstract
The voltage-gated sodium channel Na(v)1.7 plays a crucial role in pain, and drugs that inhibit hNa(v)1.7 may have tremendous therapeutic potential. ProTx-II and huwentoxin-IV (HWTX-IV), cystine knot peptides from tarantula venoms, preferentially block hNa(v)1.7. Understanding the interactions of these toxins with sodium channels could aid the development of novel pain therapeutics. Whereas both ProTx-II and HWTX-IV have been proposed to preferentially block hNa(v)1.7 activation by trapping the domain II voltage-sensor in the resting configuration, we show that specific residues in the voltage-sensor paddle of domain II play substantially different roles in determining the affinities of these toxins to hNa(v)1.7. The mutation E818C increases ProTx-II's and HWTX-IV's IC(50) for block of hNa(v)1.7 currents by 4- and 400-fold, respectively. In contrast, the mutation F813G decreases ProTx-II affinity by 9-fold but has no effect on HWTX-IV affinity. It is noteworthy that we also show that ProTx-II, but not HWTX-IV, preferentially interacts with hNa(v)1.7 to impede fast inactivation by trapping the domain IV voltage-sensor in the resting configuration. Mutations E1589Q and T1590K in domain IV each decreased ProTx-II's IC(50) for impairment of fast inactivation by ~6-fold. In contrast mutations D1586A and F1592A in domain-IV increased ProTx-II's IC(50) for impairment of fast inactivation by ~4-fold. Our results show that whereas ProTx-II and HWTX-IV binding determinants on domain-II may overlap, domain II plays a much more crucial role for HWTX-IV, and contrary to what has been proposed to be a guiding principle of sodium channel pharmacology, molecules do not have to exclusively target the domain IV voltage-sensor to influence sodium channel inactivation.
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