title: Worms take to the slo lane: a perspective on the mode of action of emodepside.
abstract: The cyclo-octapdepsipeptide anthelmintic emodepside exerts a profound paralysis on parasitic and free-living nematodes. The neuromuscular junction is a significant determinant of this effect. Pharmacological and electrophysiological analyses in the parasitic nematode Ascaris suum have resolved that emodepside elicits a hyperpolarisation of body wall muscle, which is dependent on extracellular calcium and the efflux of potassium ions. The molecular basis for emodepside's action has been investigated in forward genetic screens in the free-living nematode Caenorhabditis elegans. Two screens for emodepside resistance, totalling 20,000 genomes, identified several mutants of slo-1, which encodes a calcium-activated potassium channel homologous to mammalian BK channels. Slo-1 null mutants are more than 1000-fold less sensitive to emodepside than wild-type C. elegans and tissue-specific expression studies show emodepside acts on SLO-1 in neurons regulating feeding and motility as well as acting on SLO-1 in body wall muscle. These genetic data, combined with physiological measurements in C. elegans and the earlier physiological analyses on A. suum, define a pivotal role for SLO-1 in the mode of action of emodepside. Additional signalling pathways have emerged as determinants of emodepside's mode of action through biochemical and hypothesis-driven approaches. Mutant analyses of these pathways suggest a modulatory role for each of them in emodepside's mode of action; however, they impart much more modest changes in the sensitivity to emodepside than mutations in slo-1. Taken together these studies identify SLO-1 as the major determinant of emodepside's anthelmintic activity. Structural information on the BK channels has advanced significantly in the last 2 years. Therefore, we rationalise this possibility by suggesting a model that speculates on the nature of the emodepside pharmacophore within the calcium-activated potassium channels.
authors.affiliation: Centre for Biosciences, University of Southampton, Building 85, University Road, Southampton, SO17 1BJ, UK. lmhd@soton.ac.uk
authors.forename: Lindy
authors.initials: L
authors.lastname: Holden-Dye
authors.forename: Anna
authors.initials: A
authors.lastname: Crisford
authors.forename: Claudia
authors.initials: C
authors.lastname: Welz
authors.forename: Georg
authors.initials: G
authors.lastname: von Samson-Himmelstjerna
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Walker
authors.forename: Vincent
authors.initials: V
authors.lastname: O'Connor
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D047630:Depsipeptides / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000235:genetics* / Q000378:metabolism
chemical_list: D000871:Anthelmintics; D029742:Caenorhabditis elegans Proteins; D047630:Depsipeptides; D051036:Large-Conductance Calcium-Activated Potassium Channels; C494845:slo-1 protein, C elegans; C468987:emodepside