Publikationsdatenbank

Decreased emodepside sensitivity in unc-49 γ-aminobutyric acid (GABA)-receptor-deficient Caenorhabditis elegans (2012)

Art

Zeitschriftenartikel / wissenschaftlicher Beitrag

Autoren

Miltsch, Sandra M

Krücken, Jürgen (WE 13)

Demeler, Janina (WE 13)

Janssen, I Jana (WE 13)

Krüger, Nina

Harder, Achim

von Samson-Himmelstjerna, Georg (WE 13)

Quelle

International Journal for Parasitology; 42(8) — S. 761–770

ISSN: 0020-7519

Sprache

Englisch

Verweise

DOI: 10.1016/j.ijpara.2012.05.009

Pubmed: 22727682

Kontakt

Institut für Parasitologie und Tropenveterinärmedizin

Robert-von-Ostertag-Str. 7-13
Gebäude 35, 22, 23
14163 Berlin
Tel.+49 30 838 62310 Fax.+49 30 838 62323
email:parasitologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

Emodepside, a semi-synthetic derivative of PF1022A, belongs to a new class of anthelmintic drugs, the cyclooctadepsipeptides, and shows good efficacy against macrocyclic lactone-, levamisole- or benzimidazole-resistant nematode populations. Although putative receptors for emodepside have already been discovered, its mode of action is still not fully understood. The involvement of the γ-aminobutyric acid (GABA)-receptor on the PF1022A mode of action has previously been postulated. Therefore, a possible role of the GABA-receptor, unc-49, in the mode of action of emodepside was investigated using two different Caenorhabditis elegans in vitro assays, a motility assay and a development assay. It was found that there is a clearly reduced sensitivity against emodepside of strains carrying a GABA-receptor, unc-49, loss of function mutation compared with N2 wild type C. elegans. To transfer these results from the model system to parasitic nematodes, the Toxocara canis unc-49B cDNA sequence was identified and used in a rescue experiment. The emodepside-susceptible phenotype could be fully rescued by injection of the T. canis unc-49B cDNA sequence. We believe that this is the first functional rescue of a C. elegans mutant strain with a gene from a clade III parasitic nematode. These findings, together with the earlier data on GABA-receptor binding of PF1022A, suggest that the GABA(A)-receptor UNC-49 is associated with the emodepside mode of action. However, the only partially resistant phenotype of the loss of function mutants indicates that other pathways play a more significant role.