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Molecular Pharmacology

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Research ArticleArticle

Selective Toxicity of the Anthelmintic Emodepside Revealed by Heterologous Expression of Human KCNMA1 in Caenorhabditis elegans

Anna Crisford, Caitriona Murray, Vincent O'Connor, Richard J. Edwards, Nina Kruger, Claudia Welz, Georg von Samson-Himmelstjerna, Achim Harder, Robert J. Walker and Lindy Holden-Dye
Molecular Pharmacology June 2011, 79 (6) 1031-1043; DOI: https://doi.org/10.1124/mol.111.071043
Anna Crisford
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Caitriona Murray
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Vincent O'Connor
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Richard J. Edwards
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Nina Kruger
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Claudia Welz
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Georg von Samson-Himmelstjerna
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Achim Harder
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Robert J. Walker
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Lindy Holden-Dye
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Abstract

Emodepside is a resistance-breaking anthelmintic of a new chemical class, the cyclooctadepsipeptides. A major determinant of its anthelmintic effect is the calcium-activated potassium channel SLO-1. SLO-1 belongs to a family of channels that are highly conserved across the animal phyla and regulate neurosecretion, hormone release, muscle contraction, and neuronal network excitability. To investigate the selective toxicity of emodepside, we performed transgenic experiments in which the nematode SLO-1 channel was swapped for a mammalian ortholog, human KCNMA1. Expression of either the human channel or Caenorhabditis elegans slo-1 from the native slo-1 promoter in a C. elegans slo-1 functional null mutant rescued behavioral deficits that otherwise resulted from loss of slo-1 signaling. However, worms expressing the human channel were 10- to 100-fold less sensitive to emodepside than those expressing the nematode channel. Strains expressing the human KCNMA1 channel were preferentially sensitive to the mammalian channel agonists NS1619 and rottlerin. In the C. elegans pharyngeal nervous system, slo-1 is expressed in neurons, not muscle, and cell-specific rescue experiments have previously shown that emodepside inhibits serotonin-stimulated feeding by interfering with SLO-1 signaling in the nervous system. Here we show that ectopic overexpression of slo-1 in pharyngeal muscle confers sensitivity of the muscle to emodepside, consistent with a direct interaction of emodepside with the channel. Taken together, these data predict an emodepside-selective pharmacophore harbored by SLO-1. This has implications for the development of this drug/target interface for the treatment of helminth infections.

Footnotes

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

  • This work was supported by the Biotechnology and Biological Research Council UK [Grant BB/F009208/1] and by a postgraduate studentship from Bayer Healthcare AG.

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

    doi:10.1124/mol.111.071043.

  • ABBREVIATIONS:

    NGM
    nematode growth medium
    NCBI
    National Center for Biotechnology Information
    ORF
    open reading frame
    PCR
    polymerase chain reaction
    L4
    larval stage 4
    EPG
    electropharyngeogram
    5-HT
    5-hydroxytryptamine (serotonin)
    NS1619
    1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one
    DMSO
    dimethyl sulfoxide
    ANOVA
    analysis of variance
    BK
    large-conductance potassium channel.

  • Received January 15, 2011.
  • Accepted March 17, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (6)
Molecular Pharmacology
Vol. 79, Issue 6
1 Jun 2011
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Research ArticleArticle

Selective Toxicity of the Anthelmintic Emodepside Revealed by Heterologous Expression of Human KCNMA1 in Caenorhabditis elegans

Anna Crisford, Caitriona Murray, Vincent O'Connor, Richard J. Edwards, Nina Kruger, Claudia Welz, Georg von Samson-Himmelstjerna, Achim Harder, Robert J. Walker and Lindy Holden-Dye
Molecular Pharmacology June 1, 2011, 79 (6) 1031-1043; DOI: https://doi.org/10.1124/mol.111.071043

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Research ArticleArticle

Selective Toxicity of the Anthelmintic Emodepside Revealed by Heterologous Expression of Human KCNMA1 in Caenorhabditis elegans

Anna Crisford, Caitriona Murray, Vincent O'Connor, Richard J. Edwards, Nina Kruger, Claudia Welz, Georg von Samson-Himmelstjerna, Achim Harder, Robert J. Walker and Lindy Holden-Dye
Molecular Pharmacology June 1, 2011, 79 (6) 1031-1043; DOI: https://doi.org/10.1124/mol.111.071043
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