Resistance to levamisole resolved at the single-channel level.
Levamisole is commonly used to treat nematode parasite infections but therapy is limited by resistance. The purpose of this study was to determine the mechanism of resistance to this selective nicotinic drug. Levamisole receptor channel currents in muscle patches from levamisole-sensitive and levamisole-resistant isolates of the parasitic nematode Oesophagostomum dentatum were compared. The number of channels present in patches of sensitive and resistant isolates was similar at 10 microM levamisole, but at 30 microM and 100 microM the resistant isolate contained fewer active patches, suggesting desensitization. Mean Po and open times were reduced in resistant isolates. The distribution of conductances of channels in the sensitive isolate revealed a heterogeneous receptor population and the presence of G25, G35, G40, and G45 subtypes. A G35 subtype was missing in the resistant isolate. Resistance to levamisole was produced by changes in the averaged properties of the levamisole receptor population, with some receptors from sensitive and resistant isolates having indistinguishable characteristics.
Robertson
A P
AP
Department of Preclinical Veterinary Sciences, R.(D.)S.V.S., Summerhall, University of Edinburgh, Edinburgh EH9 1QH, U.K. alanr@lab0.vet.ed.ac.uk
Bjorn
H E
HE
Martin
R J
RJ
D000818:Animals; D000969:Antinematodal Agents / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics; D004553:Electric Conductivity; D005260:Female; D015640:Ion Channel Gating; D007473:Ion Channels / Q000378:metabolism*; D007978:Levamisole / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D009815:Oesophagostomum / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D011978:Receptors, Nicotinic / Q000378:metabolism*
D000969:Antinematodal Agents; D007473:Ion Channels; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D007978:Levamisole