acr-23 Encodes a monepantel-sensitive channel in Caenorhabditis elegans.
Monepantel is a member of the recently identified class of anthelmintics known as the amino-acetonitrile derivatives (AADs). Monepantel controls all major gastro-intestinal nematodes in sheep including those that are resistant to the classical anthelmintics. Previous studies have shown that the Caenorhabditis elegans acr-23 and the Haemonchus contortus Hco-mptl-1 genes may be prominent targets of monepantel. With this discovery it became possible to investigate the mode of action of monepantel in nematodes at the molecular level. In the present study, we show that a C. elegans mutant acr-23 strain is fully rescued by expressing the wild-type acr-23 gene. Moreover, we present a new mutant allele, and characterize acr-23 alleles genetically. We also show that acr-23 is expressed in body wall muscle cells, and provide therefore a possible explanation for the paralysis caused by monepantel. Furthermore, genetic evidence suggests that the chaperone RIC-3 is required for expression of full monepantel resistance. Finally, we present reconstitution of the C. elegans ACR-23 receptor in Xenopus laevis oocytes and provide direct evidence of its modulation by monepantel. Conversely, co-injection of the chaperone RIC-3 had no impact for channel reconstitution in X. laevis oocytes. These results reinforce the involvement of the ACR-23 family in the mode of action of monepantel and advance our understanding of this new class of anthelmintics.
Novartis Centre de Recherche Santé Animale, St. Aubin, Switzerland.
Lucien
L
Rufener
Nicola
N
Bedoni
Roland
R
Baur
Samantha
S
Rey
Dominique A
DA
Glauser
Jacques
J
Bouvier
Robin
R
Beech
Erwin
E
Sigel
Alessandro
A
Puoti
D000607:Aminoacetonitrile / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D004351:Drug Resistance / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics; D014982:Xenopus laevis
D029742:Caenorhabditis elegans Proteins; D007473:Ion Channels; D000607:Aminoacetonitrile; C533978:monepantel