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The tarantula toxins ProTx-II and huwentoxin-IV differentially interact with human Nav1.7 voltage sensors to inhibit channel activation and inactivation.
Mol Pharmacol. 2010 Dec; 78(6):1124-34.MP

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.

Authors+Show Affiliations

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

Pub Type(s)

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

Language

eng

PubMed ID

20855463

Citation

Xiao, Yucheng, et al. "The Tarantula Toxins ProTx-II and huwentoxin-IV Differentially Interact With Human Nav1.7 Voltage Sensors to Inhibit Channel Activation and Inactivation." Molecular Pharmacology, vol. 78, no. 6, 2010, pp. 1124-34.
Xiao Y, Blumenthal K, Jackson JO, et al. The tarantula toxins ProTx-II and huwentoxin-IV differentially interact with human Nav1.7 voltage sensors to inhibit channel activation and inactivation. Mol Pharmacol. 2010;78(6):1124-34.
Xiao, Y., Blumenthal, K., Jackson, J. O., Liang, S., & Cummins, T. R. (2010). The tarantula toxins ProTx-II and huwentoxin-IV differentially interact with human Nav1.7 voltage sensors to inhibit channel activation and inactivation. Molecular Pharmacology, 78(6), 1124-34. https://doi.org/10.1124/mol.110.066332
Xiao Y, et al. The Tarantula Toxins ProTx-II and huwentoxin-IV Differentially Interact With Human Nav1.7 Voltage Sensors to Inhibit Channel Activation and Inactivation. Mol Pharmacol. 2010;78(6):1124-34. PubMed PMID: 20855463.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The tarantula toxins ProTx-II and huwentoxin-IV differentially interact with human Nav1.7 voltage sensors to inhibit channel activation and inactivation. AU - Xiao,Yucheng, AU - Blumenthal,Kenneth, AU - Jackson,James O,2nd AU - Liang,Songping, AU - Cummins,Theodore R, Y1 - 2010/09/20/ PY - 2010/9/22/entrez PY - 2010/9/22/pubmed PY - 2010/12/18/medline SP - 1124 EP - 34 JF - Molecular pharmacology JO - Mol Pharmacol VL - 78 IS - 6 N2 - 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. SN - 1521-0111 UR - https://www.unboundmedicine.com/medline/citation/20855463/The_tarantula_toxins_ProTx_II_and_huwentoxin_IV_differentially_interact_with_human_Nav1_7_voltage_sensors_to_inhibit_channel_activation_and_inactivation_ L2 - http://molpharm.aspetjournals.org/cgi/pmidlookup?view=long&pmid=20855463 DB - PRIME DP - Unbound Medicine ER -