RRC ID 46180
Author Rufener L, Bedoni N, Baur R, Rey S, Glauser DA, Bouvier J, Beech R, Sigel E, Puoti A.
Title acr-23 Encodes a monepantel-sensitive channel in Caenorhabditis elegans.
Journal PLoS Pathog
Abstract 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.
Volume 9(8)
Pages e1003524
Published 2013-1-1
DOI 10.1371/journal.ppat.1003524
PMID 23950710
PMC PMC3738477
MeSH Aminoacetonitrile / analogs & derivatives* Aminoacetonitrile / pharmacology Animals Caenorhabditis elegans / genetics Caenorhabditis elegans / metabolism* Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Drug Resistance / drug effects Drug Resistance / physiology* Gene Expression Regulation / drug effects Gene Expression Regulation / genetics Ion Channels / genetics Ion Channels / metabolism* Mutation Organ Specificity / drug effects Organ Specificity / genetics Xenopus laevis
IF 6.218
Times Cited 18
C.elegans tm2804