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Research ArticleArticle

Batrachotoxin, Pyrethroids, and BTG 502 Share Overlapping Binding Sites on Insect Sodium Channels

Yuzhe Du, Daniel Garden, Bhupinder Khambay, Boris S. Zhorov and Ke Dong
Molecular Pharmacology September 2011, 80 (3) 426-433; DOI: https://doi.org/10.1124/mol.111.072504
Yuzhe Du
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Daniel Garden
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Bhupinder Khambay
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Boris S. Zhorov
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Ke Dong
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Abstract

Batrachotoxin (BTX), a steroidal alkaloid, and pyrethroid insecticides bind to distinct but allosterically coupled receptor sites on voltage-gated sodium channels and cause persistent channel activation. BTX presumably binds in the inner pore, whereas pyrethroids are predicted to bind at the lipid-exposed cavity formed by the short intracellular linker-helix IIS4-S5 and transmembrane helices IIS5 and IIIS6. The alkylamide insecticide (2E,4E)-N-(1,2-dimethylpropyl)-6-(5-bromo-2-naphthalenyl)-2,4-hexadienamide (BTG 502) reduces sodium currents and antagonizes the action of BTX on cockroach sodium channels, suggesting that it also binds inside the pore. However, a pyrethroid-sensing residue, Phe3i17 in IIIS6, which does not face the pore, is essential for the activity of BTG 502 but not for BTX. In this study, we found that three additional deltamethrin-sensing residues in IIIS6, Ile3i12, Gly3i14, and Phe3i16 (the latter two are also BTX-sensing), and three BTX-sensing residues, Ser3i15 and Leu3i19 in IIIS6 and Phe4i15 in IVS6, are all critical for BTG 502 action on cockroach sodium channels. Using these data as constraints, we constructed a BTG 502 binding model in which BTG 502 wraps around IIIS6, probably making direct contacts with all of the above residues on the opposite faces of the IIIS6 helix, except for the putative gating hinge Gly3i14. BTG 502 and its inactive analog DAP 1855 antagonize the action of deltamethrin. The antagonism was eliminated by mutations of Ser3i15, Phe3i17, Leu3i19, and Phe4i15 but not by mutations of Ile3i12, Gly3i14, and Phe3i16. Our analysis revealed a unique mode of action of BTG 502, its receptor site overlapping with those of both BTX and deltamethrin.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This study was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant GM057440] and the Natural Sciences and Engineering Research Council of Canada [Grant GRPIN/238773-2009]. Computations were performed using the facilities of the Shared Hierarchical Academic Research Computing Network (http://www.sharcnet.ca).

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.111.072504.

  • ABBREVIATIONS:

    NaV
    Voltage-gated sodium channel
    BTX
    batrachotoxin
    BTG 502
    (2E,4E)-N-(1,2-dimethylpropyl)-6-(5-bromo-2-naphthalenyl)-2,4-hexadienamide
    DMSO
    dimethyl sulfoxide
    MC
    Monte Carlo
    BgNav
    cockroach sodium channel.

  • Received March 30, 2011.
  • Accepted June 3, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (3)
Molecular Pharmacology
Vol. 80, Issue 3
1 Sep 2011
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Research ArticleArticle

Batrachotoxin, Pyrethroids, and BTG 502 Share Overlapping Binding Sites on Insect Sodium Channels

Yuzhe Du, Daniel Garden, Bhupinder Khambay, Boris S. Zhorov and Ke Dong
Molecular Pharmacology September 1, 2011, 80 (3) 426-433; DOI: https://doi.org/10.1124/mol.111.072504

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Research ArticleArticle

Batrachotoxin, Pyrethroids, and BTG 502 Share Overlapping Binding Sites on Insect Sodium Channels

Yuzhe Du, Daniel Garden, Bhupinder Khambay, Boris S. Zhorov and Ke Dong
Molecular Pharmacology September 1, 2011, 80 (3) 426-433; DOI: https://doi.org/10.1124/mol.111.072504
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