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Tarantula huwentoxin-IV inhibits neuronal sodium channels by binding to receptor site 4 and trapping the domain ii voltage sensor in the closed configuration.
J Biol Chem. 2008 Oct 03; 283(40):27300-13.JB

Abstract

Peptide toxins with high affinity, divergent pharmacological functions, and isoform-specific selectivity are powerful tools for investigating the structure-function relationships of voltage-gated sodium channels (VGSCs). Although a number of interesting inhibitors have been reported from tarantula venoms, little is known about the mechanism for their interaction with VGSCs. We show that huwentoxin-IV (HWTX-IV), a 35-residue peptide from tarantula Ornithoctonus huwena venom, preferentially inhibits neuronal VGSC subtypes rNav1.2, rNav1.3, and hNav1.7 compared with muscle subtypes rNav1.4 and hNav1.5. Of the five VGSCs examined, hNav1.7 was most sensitive to HWTX-IV (IC(50) approximately 26 nM). Following application of 1 microm HWTX-IV, hNav1.7 currents could only be elicited with extreme depolarizations (>+100 mV). Recovery of hNav1.7 channels from HWTX-IV inhibition could be induced by extreme depolarizations or moderate depolarizations lasting several minutes. Site-directed mutagenesis analysis indicated that the toxin docked at neurotoxin receptor site 4 located at the extracellular S3-S4 linker of domain II. Mutations E818Q and D816N in hNav1.7 decreased toxin affinity for hNav1.7 by approximately 300-fold, whereas the reverse mutations in rNav1.4 (N655D/Q657E) and the corresponding mutations in hNav1.5 (R812D/S814E) greatly increased the sensitivity of the muscle VGSCs to HWTX-IV. Our data identify a novel mechanism for sodium channel inhibition by tarantula toxins involving binding to neurotoxin receptor site 4. In contrast to scorpion beta-toxins that trap the IIS4 voltage sensor in an outward configuration, we propose that HWTX-IV traps the voltage sensor of domain II in the inward, closed configuration.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18628201

Citation

Xiao, Yucheng, et al. "Tarantula huwentoxin-IV Inhibits Neuronal Sodium Channels By Binding to Receptor Site 4 and Trapping the Domain Ii Voltage Sensor in the Closed Configuration." The Journal of Biological Chemistry, vol. 283, no. 40, 2008, pp. 27300-13.
Xiao Y, Bingham JP, Zhu W, et al. Tarantula huwentoxin-IV inhibits neuronal sodium channels by binding to receptor site 4 and trapping the domain ii voltage sensor in the closed configuration. J Biol Chem. 2008;283(40):27300-13.
Xiao, Y., Bingham, J. P., Zhu, W., Moczydlowski, E., Liang, S., & Cummins, T. R. (2008). Tarantula huwentoxin-IV inhibits neuronal sodium channels by binding to receptor site 4 and trapping the domain ii voltage sensor in the closed configuration. The Journal of Biological Chemistry, 283(40), 27300-13. https://doi.org/10.1074/jbc.M708447200
Xiao Y, et al. Tarantula huwentoxin-IV Inhibits Neuronal Sodium Channels By Binding to Receptor Site 4 and Trapping the Domain Ii Voltage Sensor in the Closed Configuration. J Biol Chem. 2008 Oct 3;283(40):27300-13. PubMed PMID: 18628201.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tarantula huwentoxin-IV inhibits neuronal sodium channels by binding to receptor site 4 and trapping the domain ii voltage sensor in the closed configuration. AU - Xiao,Yucheng, AU - Bingham,Jon-Paul, AU - Zhu,Weiguo, AU - Moczydlowski,Edward, AU - Liang,Songping, AU - Cummins,Theodore R, Y1 - 2008/07/14/ PY - 2008/7/17/pubmed PY - 2008/11/5/medline PY - 2008/7/17/entrez SP - 27300 EP - 13 JF - The Journal of biological chemistry JO - J Biol Chem VL - 283 IS - 40 N2 - Peptide toxins with high affinity, divergent pharmacological functions, and isoform-specific selectivity are powerful tools for investigating the structure-function relationships of voltage-gated sodium channels (VGSCs). Although a number of interesting inhibitors have been reported from tarantula venoms, little is known about the mechanism for their interaction with VGSCs. We show that huwentoxin-IV (HWTX-IV), a 35-residue peptide from tarantula Ornithoctonus huwena venom, preferentially inhibits neuronal VGSC subtypes rNav1.2, rNav1.3, and hNav1.7 compared with muscle subtypes rNav1.4 and hNav1.5. Of the five VGSCs examined, hNav1.7 was most sensitive to HWTX-IV (IC(50) approximately 26 nM). Following application of 1 microm HWTX-IV, hNav1.7 currents could only be elicited with extreme depolarizations (>+100 mV). Recovery of hNav1.7 channels from HWTX-IV inhibition could be induced by extreme depolarizations or moderate depolarizations lasting several minutes. Site-directed mutagenesis analysis indicated that the toxin docked at neurotoxin receptor site 4 located at the extracellular S3-S4 linker of domain II. Mutations E818Q and D816N in hNav1.7 decreased toxin affinity for hNav1.7 by approximately 300-fold, whereas the reverse mutations in rNav1.4 (N655D/Q657E) and the corresponding mutations in hNav1.5 (R812D/S814E) greatly increased the sensitivity of the muscle VGSCs to HWTX-IV. Our data identify a novel mechanism for sodium channel inhibition by tarantula toxins involving binding to neurotoxin receptor site 4. In contrast to scorpion beta-toxins that trap the IIS4 voltage sensor in an outward configuration, we propose that HWTX-IV traps the voltage sensor of domain II in the inward, closed configuration. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/18628201/Tarantula_huwentoxin_IV_inhibits_neuronal_sodium_channels_by_binding_to_receptor_site_4_and_trapping_the_domain_ii_voltage_sensor_in_the_closed_configuration_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0021-9258(20)73494-0 DB - PRIME DP - Unbound Medicine ER -