title: Selective toxicity of the anthelmintic emodepside revealed by heterologous expression of human KCNMA1 in Caenorhabditis elegans.
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.
authors.affiliation: School of Biological Sciences, University of Southampton, Highfield Campus, Southampton SO17 1BJ, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Crisford
authors.forename: Caitriona
authors.initials: C
authors.lastname: Murray
authors.forename: Vincent
authors.initials: V
authors.lastname: O'Connor
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Edwards
authors.forename: Nina
authors.initials: N
authors.lastname: Kruger
authors.forename: Claudia
authors.initials: C
authors.lastname: Welz
authors.forename: Georg
authors.initials: G
authors.lastname: von Samson-Himmelstjerna
authors.forename: Achim
authors.initials: A
authors.lastname: Harder
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Walker
authors.forename: Lindy
authors.initials: L
authors.lastname: Holden-Dye
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000871:Anthelmintics / Q000633:toxicity*; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000502:physiology; D047630:Depsipeptides / Q000633:toxicity*; D006801:Humans; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000235:genetics*; D008124:Locomotion; D024681:Potassium Channels, Calcium-Activated / Q000819:agonists
chemical_list: D000871:Anthelmintics; D047630:Depsipeptides; C494841:KCNMA1 protein, human; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D024681:Potassium Channels, Calcium-Activated; C468987:emodepside