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Molecular Pharmacology

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Research ArticleArticle

Mammalian Skeletal Muscle Voltage-Gated Sodium Channels Are Affected by Scorpion Depressant “Insect-Selective” Toxins when Preconditioned

Lior Cohen, Yael Troub, Michael Turkov, Nicolas Gilles, Nitza Ilan, Morris Benveniste, Dalia Gordon and Michael Gurevitz
Molecular Pharmacology November 2007, 72 (5) 1220-1227; DOI: https://doi.org/10.1124/mol.107.039057
Lior Cohen
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Yael Troub
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Michael Turkov
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Nicolas Gilles
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Nitza Ilan
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Morris Benveniste
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Dalia Gordon
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Michael Gurevitz
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Abstract

Among scorpion β- and α-toxins that modify the activation and inactivation of voltage-gated sodium channels (Navs), depressant β-toxins have traditionally been classified as anti-insect selective on the basis of toxicity assays and lack of binding and effect on mammalian Navs. Here we show that the depressant β-toxins LqhIT2 and Lqh-dprIT3 from Leiurus quinquestriatus hebraeus (Lqh) bind with nanomolar affinity to receptor site 4 on rat skeletal muscle Navs, but their effect on the gating properties can be viewed only after channel preconditioning, such as that rendered by a long depolarizing prepulse. This observation explains the lack of toxicity when depressant toxins are injected in mice. However, when the muscle channel rNav1.4, expressed in Xenopus laevis oocytes, was modulated by the site 3 α-toxin LqhαIT, LqhIT2 was capable of inducing a negative shift in the voltage-dependence of activation after a short prepulse, as was shown for other β-toxins. These unprecedented results suggest that depressant toxins may have a toxic impact on mammals in the context of the complete scorpion venom. To assess whether LqhIT2 and Lqh-dprIT3 interact with the insect and rat muscle channels in a similar manner, we examined the role of Glu24, a conserved “hot spot” at the bioactive surface of β-toxins. Whereas substitutions E24A/N abolished the activity of both LqhIT2 and Lqh-dprIT3 at insect Navs, they increased the affinity of the toxins for rat skeletal muscle channels. This result implies that depressant toxins interact differently with the two channel types and that substitution of Glu24 is essential for converting toxin selectivity.

Footnotes

  • This research was supported by the United States-Israel Binational Agricultural Research and Development grants IS-3928-06 (to M.G. and D.G.) and IS-4066-07 (to D.G. and M.G.); by the Israeli Science Foundation grants 909/04 (to M.G.), 1008/05 (to D.G.), 654/02 (to M.B.); by a grant from the German-Israeli Foundation (to G.I.F.) for Scientific Research and Development [G-770-242.1/2002 (D.G.); and by National Institutes of Health grant U01-NS058039-01 (to M.G.)].

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

  • doi:10.1124/mol.107.039057.

  • ABBREVIATIONS: Navs, voltage-gated sodium channels; Css4, Centruroides suffusus suffusus toxin 4; LqhIT2 and Lqh-dprIT3, Leiurus quinquestriatus hebraeus anti-insect depressant toxins; PP, preconditioning depolarizing prepulse.

  • ↵1 Current affiliation: Neuroscience Institute, Morehouse School of Medicine, Atlanta, Georgia.

    • Received June 14, 2007.
    • Accepted August 23, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 72 (5)
Molecular Pharmacology
Vol. 72, Issue 5
1 Nov 2007
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Research ArticleArticle

Mammalian Skeletal Muscle Voltage-Gated Sodium Channels Are Affected by Scorpion Depressant “Insect-Selective” Toxins when Preconditioned

Lior Cohen, Yael Troub, Michael Turkov, Nicolas Gilles, Nitza Ilan, Morris Benveniste, Dalia Gordon and Michael Gurevitz
Molecular Pharmacology November 1, 2007, 72 (5) 1220-1227; DOI: https://doi.org/10.1124/mol.107.039057

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Research ArticleArticle

Mammalian Skeletal Muscle Voltage-Gated Sodium Channels Are Affected by Scorpion Depressant “Insect-Selective” Toxins when Preconditioned

Lior Cohen, Yael Troub, Michael Turkov, Nicolas Gilles, Nitza Ilan, Morris Benveniste, Dalia Gordon and Michael Gurevitz
Molecular Pharmacology November 1, 2007, 72 (5) 1220-1227; DOI: https://doi.org/10.1124/mol.107.039057
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