The tarantula toxins ProTx-II and huwentoxin-IV differentially interact with human Nav1.7 voltage sensors to inhibit channel activation and inactivation

Yucheng Xiao, Kenneth Blumenthal, James O. Jackson, Songping Liang, Theodore R. Cummins

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

The voltage-gated sodium channel Nav1.7 plays a crucial role in pain, and drugs that inhibit hNav1.7 may have tremendous therapeutic potential. ProTx-II and huwentoxin-IV (HWTX-IV), cystine knot peptides from tarantula venoms, preferentially block hNav1.7. 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 hNav1.7 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 hNav1.7. The mutation E818C increases ProTx-II's and HWTX-IV's IC50 for block of hNa v1.7 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 hNav1.7 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 IC50 for impairment of fast inactivation by ∼6-fold. In contrast mutations D1586A and F1592A in domain-IV increased ProTx-II's IC50 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.

Original languageEnglish (US)
Pages (from-to)1124-1134
Number of pages11
JournalMolecular Pharmacology
Volume78
Issue number6
DOIs
StatePublished - Dec 1 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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