title: On the mode of action of emodepside: slow effects on membrane potential and voltage-activated currents in Ascaris suum.
abstract: OBJECTIVE
  Anthelmintics are required for treatment and prophylaxis of nematode parasites of humans and domestic animals. Emodepside, a cyclooctadepsipeptide, is a modern anthelmintic that has a novel mode of action involving a Ca-activated K channel (SLO-1) in Caenorhabditis elegans, sometimes mediated by a latrophilin (LAT) receptor. We examined mechanisms of action of emodepside in a parasitic nematode, Ascaris suum.
  
  
  METHODS
  RT-PCR was used to investigate expression of slo-1 and lat-1 in A. suum muscle flaps, and two-micropipette current-clamp and voltage-clamp techniques were used to record electrophysiological effects of emodepside.
  
  
  RESULTS
  Expression of slo-1 and lat-1 were detected. Emodepside produced a slow time-dependent (20 min), 4-aminopyridine sensitive, concentration-dependent hyperpolarization and increase in voltage-activated K currents. Sodium nitroprusside increased the hyperpolarizations and K currents. N-nitro-L-arginine inhibited the hyperpolarizations and K currents. Phorbol-12-myristate-13 acetate increased the K currents, while staurosporine inhibited the hyperpolarizations and K currents. Iberiotoxin reduced these emodepside K currents. The effect of emodepside was reduced in Ca-free solutions. Emodepside had no effect on voltage-activated Ca currents.
  
  
  CONCLUSIONS
  Asu-slo-1 and Asu-lat-1 are expressed in adult A. suum muscle flaps and emodepside produces slow activation of voltage-activated Ca-dependent SLO-1-like K channels. The effect of emodepside was enhanced by stimulation of protein kinase C and NO pathways. The data are consistent with a model in which NO, PKC and emodepside signalling pathways are separate and converge on the K channels, or in which emodepside activates NO and PKC signalling pathways to increase opening of the K channels.
authors.affiliation: Department of Biomedical Sciences, Iowa State University, Ames, IA, USA.
authors.forename: S K
authors.initials: SK
authors.lastname: Buxton
authors.forename: C
authors.initials: C
authors.lastname: Neveu
authors.forename: C L
authors.initials: CL
authors.lastname: Charvet
authors.forename: A P
authors.initials: AP
authors.lastname: Robertson
authors.forename: R J
authors.initials: RJ
authors.lastname: Martin
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology; D017165:Ascaris suum; D002118:Calcium / Q000378:metabolism; D047630:Depsipeptides / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects*; D009132:Muscles / Q000187:drug effects / Q000378:metabolism; D009589:Nitrogen Oxides / Q000378:metabolism; D018408:Patch-Clamp Techniques / Q000379:methods; D010455:Peptides / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D018000:Receptors, Peptide / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000871:Anthelmintics; D047630:Depsipeptides; D009589:Nitrogen Oxides; D010455:Peptides; D024681:Potassium Channels, Calcium-Activated; D024642:Potassium Channels, Voltage-Gated; D018000:Receptors, Peptide; C034800:alpha-latrotoxin receptor; C064719:iberiotoxin; D015761:4-Aminopyridine; D011493:Protein Kinase C; D002118:Calcium; C468987:emodepside