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Selective toxicity of the anthelmintic emodepside revealed by heterologous expression of human KCNMA1 in caenorhabditis elegans

By 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

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 orthologue, human KCNMA1. Expression of either the human channel or C. elegans slo-1 from the native slo-1 promoter in a C. elegans slo- functional null rescued behavioural deficits that otherwise resulted from loss of slo-1 signalling. 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 neurones not muscle and cell specific rescue experiments have previously shown that emodepside inhibits serotonin-stimulated feeding by interfering with SLO-1 signalling in the nervous system. Here we show that ectopic over-expression 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 harboured by SLO-1. This has implications for the development of this drug/target interface for the treatment of helminth infection

Topics: QD, R1
Year: 2011
OAI identifier: oai:eprints.soton.ac.uk:180031
Provided by: e-Prints Soton
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