A potent blocker of Neuronal TTX-Sensitive Voltage-Gated Na+ Channel that preferentially inhibits neuronal voltage-gated sodium channel subtype hNav1.7 (SCN9A) (IC50 = 26 nM), rNav1.2 (SCN2A) (IC50 = 150 nM), and rNav1.3 (SCN3A) (IC50 = 338 nM), compared with muscle subtypes rNav1.4 (SCN4A) and hNav1.5 (SCN5A) (IC50 > 10 µM). Huwentoxin IV inhibits the activation of sodium channels by trapping the voltage sensor of domain II of the site 4 in the inward, closed configuration.
CAT No: R0984
CAS No:526224-73-7
Synonyms/Alias:526224-73-7;Huwentoxin-IV;Huwentoxin IV (Selenocosmia huwena venom);Huwentoxin IV;Huwentoxin IV TFA;BWA22473;AKOS024458310;DA-54140;PD079747;
Huwentoxin IV is a peptide neurotoxin originally isolated from the venom of the Chinese bird spider Ornithoctonus huwena, renowned for its potent and selective activity on voltage-gated sodium channels. As a disulfide-rich peptide, it features a well-defined inhibitory cystine knot motif, contributing to its notable stability and specificity in modulating neuronal excitability. Its unique pharmacological profile has made it a valuable biochemical tool for dissecting the functional architecture of ion channels, particularly in the context of neuronal signaling and pain transduction pathways. The ability of Huwentoxin IV to selectively target specific sodium channel subtypes has positioned it at the forefront of neurophysiological research, offering insights into the molecular mechanisms underlying excitability and synaptic transmission.
Ion channel research: Huwentoxin IV serves as a powerful molecular probe for the study of voltage-gated sodium channels, especially Nav1.7 and Nav1.6 subtypes. By binding with high affinity and selectivity, it enables researchers to dissect the structure-function relationship of these channels, facilitating the identification of critical amino acid residues involved in gating and ion selectivity. Its use in electrophysiological assays allows for the precise characterization of channel kinetics, gating mechanisms, and pharmacological modulation, supporting a deeper understanding of neuronal excitability and conduction.
Pain pathway investigation: The selective inhibition of Nav1.7 by this peptide makes it instrumental in elucidating the molecular basis of pain signaling. It is widely employed in preclinical neurobiology to parse the contributions of sodium channel subtypes to nociceptive processing, aiding in the identification of potential molecular targets for pain modulation. Through in vitro and ex vivo nerve preparations, it helps delineate the specific roles of sodium channels in sensory neuron excitability, advancing the study of pain mechanisms at the cellular and molecular levels.
Peptide structure-function studies: As a representative member of spider-venom-derived inhibitory cystine knot peptides, Huwentoxin IV is frequently used in structural biology to investigate peptide folding, disulfide connectivity, and conformational stability. Its well-defined tertiary structure provides an excellent template for NMR spectroscopy, X-ray crystallography, and molecular modeling approaches. These studies not only inform the design of novel peptide analogs with tailored pharmacological profiles but also contribute to the understanding of peptide engineering principles relevant to drug discovery and synthetic biology.
Selective toxin screening: The high specificity of Huwentoxin IV for certain sodium channel isoforms makes it a reference standard in toxin screening assays. It is utilized to benchmark the selectivity and potency of newly discovered or engineered peptide toxins, enabling comparative studies that inform both basic research and applied toxinology. Such applications are crucial for the development of more refined research tools and for expanding the repertoire of neuroactive compounds used in ion channel research.
Peptide synthesis and modification: The complex disulfide-rich structure of Huwentoxin IV presents a challenging yet informative model for peptide chemists engaged in solid-phase peptide synthesis and oxidative folding studies. Its synthesis and subsequent folding protocols are employed to optimize methodologies for producing stable, bioactive peptides with intricate tertiary structures. Insights gained from these efforts contribute to advancing peptide manufacturing techniques and support the development of synthetic analogs for diverse research applications.
Huwentoxin-IV (HWTX-IV), similarly to JZTX-34, inhibited neuronal TTX-sensitive voltage-gated sodium channels with an IC50 value of 30 nM in adult rat dorsal root ganglion neurons (DRG neurons), but have no significant effect on TTX-resistant voltage-gated sodium channels. Recently studies demonstrated that ProTx-II and HWTX-IV binding determinants on domain-II may overlap, with domain II playing a much more crucial role for HWTX-IV. The date also proved that the inhibition of sodium currents could be reversible by strong depolarization due to the dissociation of HWTX-IV.
Native Pyroglutamation of Huwentoxin-IV: A Post-Translational Modification that Increases the Trapping Ability to the Sodium Channel
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