Haemonchus contortus: HcGluCla expressed in Xenopus oocytes forms a glutamate-gated ion channel that is activated by ibotenate and the antiparasitic drug ivermectin.
Ion channels are targets for many drugs including insecticides and anthelminthic agents such as ivermectin (IVM) and moxidectin (MOX). IVM has been shown to activate glutamate-gated chloride channels (GluCls) from the free-living nematode, Caenorhabditis elegans. Haemonchus contortus is a parasitic nematode that is also extremely sensitive to IVM. The high sensitivity of H. contortus to IVM is probably the result of the fact that, like C. elegans, H. contortus also express GluCls. To investigate the potential physiological response to IVM in H. contortus we have expressed a GluCl from this parasite (H. contortus glutamate-gated chloride channel, HcGluCla) in Xenopus oocytes. HcGluCla expressed in oocytes formed a homomeric channel that responded to glutamate and ibotenate as well as the anthelmintics IVM and MOX. The response to glutamate and ibotenate was fast acting and reversible whereas the response to IVM and MOX was a slower activating channel that was essentially irreversible. These results suggest that IVM toxicity in H. contortus is the result of its irreversible activation of GluCls.
Forrester
Sean G
SG
Institute of Parasitology, McGill University, 21,111 Lakeshore Road, Quebec, Ste-Anne de Bellevue, Canada H9X 3V9. sgforrester@yahoo.ca
Prichard
Roger K
RK
Dent
Joseph A
JA
Beech
Robin N
RN
D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D006189:Haemonchus / Q000235:genetics; D015801:Helminth Proteins / Q000235:genetics / Q000378:metabolism*; D007051:Ibotenic Acid / Q000494:pharmacology*; D007559:Ivermectin / Q000494:pharmacology*; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D014158:Transcription, Genetic; D014982:Xenopus laevis
D000871:Anthelmintics; D018118:Chloride Channels; D015801:Helminth Proteins; C109777:glutamate-gated chloride channels; D007051:Ibotenic Acid; D007559:Ivermectin