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  2. On the mode of action of emodepside: slow effects on membrane potential and voltage-activated currents in Ascaris suum

On the mode of action of emodepside: slow effects on membrane potential and voltage-activated currents in Ascaris suum

  • Br J Pharmacol. 2011 Sep;164(2b):453-70. doi: 10.1111/j.1476-5381.2011.01428.x.
S K Buxton 1 C Neveu C L Charvet A P Robertson R J Martin
Affiliations

Affiliation

  • 1 Department of Biomedical Sciences, Iowa State University, Ames, IA, USA.
Abstract

Background and purpose: 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.

Experimental approach: 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.

Key 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 and implications: 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.

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