Anthelmintic actions on homomer-forming nicotinic acetylcholine receptor subunits: chicken alpha7 and ACR-16 from the nematode Caenorhabditis elegans.
Two homomer-forming nicotinic acetylcholine receptor subunits with 47% identity in their amino acid sequences were employed to compare the actions of cholinergic anthelmintics and ivermectin on expressed vertebrate and nematode nicotinic receptors of known molecular composition. Voltage-clamp electrophysiology was used to study recombinant nicotinic receptors expressed in Xenopus laevis oocytes following nuclear injection of cDNA encoding either chicken alpha7 or Caenorhabditis elegans ACR-16 (Ce21) subunits. Butamisole, morantel and metyridine were without agonist actions on either alpha7 or ACR-16 nicotinic receptors in the range 10nM-1mM. However, butamisole (pIC(50)=4.9 for both alpha7 and ACR-16) and morantel (pIC(50)=5.6 for alpha7 and 5.7 for ACR-16) antagonized responses of both alpha7 and ACR-16 receptors to acetylcholine. Metyridine (1mM) did not affect responses to acetylcholine of either receptor. Oxantel was without agonist actions on ACR-16, but was an acetylcholine antagonist (pIC(50)=5.4). In contrast, it was found to have low efficacy agonist action (pEC(50)=4.4) on alpha7 at concentrations in the range 10-300microM. In agreement with a previous study, ivermectin (30microM), an agonist of L-glutamate-gated chloride channels, enhanced the amplitude of responses to acetylcholine of alpha7 nicotinic receptors. However, this same concentration of ivermectin (30microM) did not potentiate the acetylcholine-induced responses of ACR-16, but rather resulted in a slight attenuation. We conclude that oxantel and ivermectin have identified new pharmacological differences between the chicken alpha7 nicotinic receptor and its C. elegans homologue ACR-16.
Raymond
V
V
MRC Functional Genetics Unit, Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, OX1 3QX, Oxford, UK.
Mongan
N P
NP
Sattelle
D B
DB
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D002645:Chickens / Q000378:metabolism*; D018076:DNA, Complementary / Q000187:drug effects / Q000502:physiology; D005260:Female; D007559:Ivermectin / Q000494:pharmacology; D009015:Morantel / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D011715:Pyrantel / Q000031:analogs & derivatives* / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D017385:Sequence Homology; D013844:Thiazoles / Q000494:pharmacology; D014982:Xenopus laevis / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
D000871:Anthelmintics; C579167:Chrna7 protein, human; D018076:DNA, Complementary; D011725:Pyridines; D011978:Receptors, Nicotinic; D013844:Thiazoles; D064569:alpha7 Nicotinic Acetylcholine Receptor; C100211:methyridine; D011715:Pyrantel; D007559:Ivermectin; D009015:Morantel; C003407:oxantel; D000109:Acetylcholine; C020238:butamisole