Anthelmintic actions on homomer-forming nicotinic acetylcholine receptor subunits: chicken alpha 7 and ACR-16 from the nematode Caenorhabditis elegans

Two homomer-forming nicotinic acetylcholine receptor subunits with 47% iden tity in their amino acid sequences were employed to compare the actions of cholinergic anthelmintics and ivermectin on expressed vertebrate and nemato de nicotinic receptors of known molecular composition. Voltage-clamp electr ophysiology 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 10 nM-1 mM. However, butamisole (pI C(50) = 4.9 for both alpha7 and ACR-16) and morantel (PIC50 = 5.6 for alpha 7 and 5.7 for ACR-16) antagonized responses of both alpha7 and ACR-16 recep tors to acetylcholine. Metyridine (1 mM) did not affect responses to acetyl choline of either receptor. Oxantel was without agonist actions on ACR-16, but was an acetylcholine antagonist (pIC(50) = 5.4). In contrast, it was fo und to have low efficacy agonist action (pEC(50) = 4.4) on alpha7 at concen trations in the range 10-300 muM. In agreement with a previous study, iverm ectin (30 muM), 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 (30 muM) did not potentiate the acetylcholine-induced responses of ACR-16, but rather resulted in a sl ight attenuation. We conclude that oxantel and ivermectin have identified new pharmacological differences between the chicken alpha7 nicotinic receptor and its C. elega ns homologue ACR-16. (C) 2000 IBRO. Published by Elsevier Science Ltd. All rights reserved.