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Molecular Pharmacology

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Research ArticleArticle

Role of the Local Anesthetic Receptor in the State-Dependent Inhibition of Voltage-Gated Sodium Channels by the Insecticide Metaflumizone

Richard T. von Stein and David M. Soderlund
Molecular Pharmacology March 2012, 81 (3) 366-374; DOI: https://doi.org/10.1124/mol.111.075283
Richard T. von Stein
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David M. Soderlund
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Abstract

Sodium channel inhibitor (SCI) insecticides selectively target voltage-gated sodium (Nav) channels in the slow-inactivated state by binding at or near the local anesthetic receptor within the sodium channel pore. Metaflumizone is a new insecticide for the treatment of fleas on domesticated pets and has recently been reported to block insect sodium channels in the slow-inactivated state, thereby implying that it is also a member of the SCI class. Using the two-electrode voltage-clamp technique, we examined metaflumizone inhibition of rat Nav1.4 sodium channels expressed in Xenopus laevis oocytes. Metaflumizone selectively inhibited Nav1.4 channels at potentials that promoted slow inactivation and shifted the voltage dependence of slow inactivation in the direction of hyperpolarization. Metaflumizone perfusion at a hyperpolarized holding potential also shifted the conductance-voltage curve for activation in the direction of depolarization and antagonized use-dependent lidocaine inhibition of fast-inactivated sodium channels, actions not previously observed with other SCI insecticides. We expressed mutated Nav1.4/F1579A and Nav1.4/Y1586A channels to investigate whether metaflumizone shares the domain IV segment S6 (DIV-S6) binding determinants identified for other SCI insecticides. Consistent with previous investigations of SCI insecticides on rat Nav1.4 channels, the F1579A mutation reduced sensitivity to block by metaflumizone, whereas the Y1586A mutation paradoxically increased the sensitivity to metaflumizone. We conclude that metaflumizone selectively inhibits slow-inactivated Nav1.4 channels and shares DIV-S6 binding determinants with other SCI insecticides and therapeutic drugs. However, our results suggest that metaflumizone interacts with resting and fast-inactivated channels in a manner that is distinct from other compounds in this insecticide class.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Environmental Health Sciences [Grant R01-ES014591].

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

    http://dx.doi.org/10.1124/mol.111.075283.

  • ABBREVIATIONS:

    SCI
    sodium channel inhibitor
    Nav
    voltage-gated sodium
    DCJW
    decarbomethoxylated (S)-methyl 7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-(trifluoromethoxy)phenyl]amino]carbonyl]indeno]1,2-e][1,3,4]oxadiazine-4a(3H)-carboxylate
    RH-4841
    N,3-bis(4-chlorophenyl)-4,5-dihydro-4-phenyl-1H-pyrazole-1-carboxamide
    LA
    local anesthetic
    DIV-S6
    domain IV segment S6
    DMSO
    dimethyl sulfoxide.

  • Received August 15, 2011.
  • Accepted November 29, 2011.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 81 (3)
Molecular Pharmacology
Vol. 81, Issue 3
1 Mar 2012
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Research ArticleArticle

Metaflumizone Action at Local Anesthetic Receptor

Richard T. von Stein and David M. Soderlund
Molecular Pharmacology March 1, 2012, 81 (3) 366-374; DOI: https://doi.org/10.1124/mol.111.075283

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Research ArticleArticle

Metaflumizone Action at Local Anesthetic Receptor

Richard T. von Stein and David M. Soderlund
Molecular Pharmacology March 1, 2012, 81 (3) 366-374; DOI: https://doi.org/10.1124/mol.111.075283
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