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.