RRC ID |
46180
|
著者 |
Rufener L, Bedoni N, Baur R, Rey S, Glauser DA, Bouvier J, Beech R, Sigel E, Puoti A.
|
タイトル |
acr-23 Encodes a monepantel-sensitive channel in Caenorhabditis elegans.
|
ジャーナル |
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.
|
巻・号 |
9(8)
|
ページ |
e1003524
|
公開日 |
2013-1-1
|
DOI |
10.1371/journal.ppat.1003524
|
PII |
PPATHOGENS-D-13-00453
|
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
|
引用数 |
18
|
WOS 分野
|
PARASITOLOGY
MICROBIOLOGY
VIROLOGY
|
リソース情報 |
線虫 |
tm2804 |