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    Characterization of the Ca2+-gated and voltage-dependent K+-channel Slo-1 of nematodes and its interaction with emodepside (2014)

    Art
    Zeitschriftenartikel / wissenschaftlicher Beitrag
    Autoren
    Kulke, Daniel (WE 13)
    von Samson-Himmelstjerna, Georg (WE 13)
    Miltsch, Sandra M (WE 13)
    Wolstenholme, Adrian J
    Jex, Aaron R
    Gasser, Robin B
    Ballesteros, Cristina
    Geary, Timothy G
    Keiser, Jennifer
    Townson, Simon
    Harder, Achim
    Krücken, Jürgen (WE 13)
    Quelle
    PLoS Neglected Tropical Diseases; 8(12) — S. e3401
    ISSN: 1935-2727
    Sprache
    Englisch
    Verweise
    URL (Volltext): http://edocs.fu-berlin.de/docs/receive/FUDOCS_document_000000021781
    DOI: 10.1371/journal.pntd.0003401
    Pubmed: 25521608
    Kontakt
    Institut für Parasitologie und Tropenveterinärmedizin

    Robert-von-Ostertag-Str. 7-13
    Gebäude 35, 22, 23
    14163 Berlin
    +49 30 838 62310
    parasitologie@vetmed.fu-berlin.de

    Abstract / Zusammenfassung

    The cyclooctadepsipeptide emodepside and its parent compound PF1022A are broad-spectrum nematicidal drugs which are able to eliminate nematodes resistant to other anthelmintics. The mode of action of cyclooctadepsipeptides is only partially understood, but involves the latrophilin Lat-1 receptor and the voltage- and calcium-activated potassium channel Slo-1. Genetic evidence suggests that emodepside exerts its anthelmintic activity predominantly through Slo-1. Indeed, slo-1 deficient Caenorhabditis elegans strains are completely emodepside resistant. However, direct effects of emodepside on Slo-1 have not been reported and these channels have only been characterized for C. elegans and related Strongylida. Molecular and bioinformatic analyses identified full-length Slo-1 cDNAs of Ascaris suum, Parascaris equorum, Toxocara canis, Dirofilaria immitis, Brugia malayi, Onchocerca gutturosa and Strongyloides ratti. Two paralogs were identified in the trichocephalids Trichuris muris, Trichuris suis and Trichinella spiralis. Several splice variants encoding truncated channels were identified in Trichuris spp. Slo-1 channels of trichocephalids form a monophyletic group, showing that duplication occurred after the divergence of Enoplea and Chromadorea. To explore the function of a representative protein, C. elegans Slo-1a was expressed in Xenopus laevis oocytes and studied in electrophysiological (voltage-clamp) experiments. Incubation of oocytes with 1-10 µM emodepside caused significantly increased currents over a wide range of step potentials in the absence of experimentally increased intracellular Ca2+, suggesting that emodepside directly opens C. elegans Slo-1a. Emodepside wash-out did not reverse the effect and the Slo-1 inhibitor verruculogen was only effective when applied before, but not after, emodepside. The identification of several splice variants and paralogs in some parasitic nematodes suggests that there are substantial differences in channel properties among species. Most importantly, this study showed for the first time that emodepside directly opens a Slo-1 channel, significantly improving the understanding of the mode of action of this drug class.