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http://purl.uniprot.org/citations/20855463http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/20855463http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/20855463http://www.w3.org/2000/01/rdf-schema#comment"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."xsd:string
http://purl.uniprot.org/citations/20855463http://purl.org/dc/terms/identifier"doi:10.1124/mol.110.066332"xsd:string
http://purl.uniprot.org/citations/20855463http://purl.org/dc/terms/identifier"doi:10.1124/mol.110.066332"xsd:string
http://purl.uniprot.org/citations/20855463http://purl.uniprot.org/core/author"Liang S."xsd:string
http://purl.uniprot.org/citations/20855463http://purl.uniprot.org/core/author"Liang S."xsd:string
http://purl.uniprot.org/citations/20855463http://purl.uniprot.org/core/author"Xiao Y."xsd:string
http://purl.uniprot.org/citations/20855463http://purl.uniprot.org/core/author"Xiao Y."xsd:string
http://purl.uniprot.org/citations/20855463http://purl.uniprot.org/core/author"Cummins T.R."xsd:string
http://purl.uniprot.org/citations/20855463http://purl.uniprot.org/core/author"Cummins T.R."xsd:string
http://purl.uniprot.org/citations/20855463http://purl.uniprot.org/core/author"Blumenthal K."xsd:string
http://purl.uniprot.org/citations/20855463http://purl.uniprot.org/core/author"Blumenthal K."xsd:string
http://purl.uniprot.org/citations/20855463http://purl.uniprot.org/core/author"Jackson J.O. II"xsd:string
http://purl.uniprot.org/citations/20855463http://purl.uniprot.org/core/author"Jackson J.O. II"xsd:string
http://purl.uniprot.org/citations/20855463http://purl.uniprot.org/core/date"2010"xsd:gYear
http://purl.uniprot.org/citations/20855463http://purl.uniprot.org/core/date"2010"xsd:gYear
http://purl.uniprot.org/citations/20855463http://purl.uniprot.org/core/name"Mol. Pharmacol."xsd:string
http://purl.uniprot.org/citations/20855463http://purl.uniprot.org/core/name"Mol. Pharmacol."xsd:string
http://purl.uniprot.org/citations/20855463http://purl.uniprot.org/core/pages"1124-1134"xsd:string
http://purl.uniprot.org/citations/20855463http://purl.uniprot.org/core/pages"1124-1134"xsd:string
http://purl.uniprot.org/citations/20855463http://purl.uniprot.org/core/title"The tarantula toxins ProTx-II and huwentoxin-IV differentially interact with human Nav1.7 voltage sensors to inhibit channel activation and inactivation."xsd:string
http://purl.uniprot.org/citations/20855463http://purl.uniprot.org/core/title"The tarantula toxins ProTx-II and huwentoxin-IV differentially interact with human Nav1.7 voltage sensors to inhibit channel activation and inactivation."xsd:string
http://purl.uniprot.org/citations/20855463http://purl.uniprot.org/core/volume"78"xsd:string
http://purl.uniprot.org/citations/20855463http://purl.uniprot.org/core/volume"78"xsd:string
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