%0 Journal Article
%T The Cyclooctadepsipeptide Anthelmintic Emodepside Differentially Modulates Nematode, Insect and Human Calcium-Activated Potassium (SLO) Channel Alpha Subunits
%A Achim Harder
%A Anna Crisford
%A Eva Schoenhense
%A Ita O¡¯Kelly
%A Kelechi Ndukwe
%A Klaus Raming
%A Lindy Holden-Dye
%A Robert J. Walker
%A Ulrich Ebbinghaus-Kintscher
%A Vincent O¡¯Connor
%J -
%D 2015
%R 10.1371/journal.pntd.0004062
%X The anthelmintic emodepside paralyses adult filarial worms, via a mode of action distinct from previous anthelmintics and has recently garnered interest as a new treatment for onchocerciasis. Whole organism data suggest its anthelmintic action is underpinned by a selective activation of the nematode isoform of an evolutionary conserved Ca2+-activated K+ channel, SLO-1. To test this at the molecular level we compared the actions of emodepside at heterologously expressed SLO-1 alpha subunit orthologues from nematode (Caenorhabditis elegans), Drosophila melanogaster and human using whole cell voltage clamp. Intriguingly we found that emodepside modulated nematode (Ce slo-1), insect (Drosophila, Dm slo) and human (hum kcnma1)SLO channels but that there are discrete differences in the features of the modulation that are consistent with its anthelmintic efficacy. Nematode SLO-1 currents required 100 ¦ÌM intracellular Ca2+ and were strongly facilitated by emodepside (100 nM; +73.0 ¡À 17.4%; n = 9; p<0.001). Drosophila Slo currents on the other hand were activated by emodepside (10 ¦ÌM) in the presence of 52 nM Ca2+ but were inhibited in the presence of 290 nM Ca2+ and exhibited a characteristic loss of rectification. Human Slo required 300nM Ca2+ and emodepside transiently facilitated currents (100nM; +33.5 ¡À 9%; n = 8; p<0.05) followed by a sustained inhibition (-52.6 ¡À 9.8%; n = 8; p<0.001). This first cross phyla comparison of the actions of emodepside at nematode, insect and human channels provides new mechanistic insight into the compound¡¯s complex modulation of SLO channels. Consistent with whole organism behavioural studies on C. elegans, it indicates its anthelmintic action derives from a strong activation of SLO current, not observed in the human channel. These data provide an important benchmark for the wider deployment of emodepside as an anthelmintic treatment
%K Caenorhabditis elegans
%K Membrane potential
%K Potassium channels
%K CHO cells
%K Drosophila melanogaster
%K Transfection
%K Insects
%K Calcium-activated potassium channels
%U https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0004062