Monepantel allosterically activates DEG-3/DES-2 channels of the gastrointestinal nematode Haemonchus contortus

Rufener, Lucien; Baur, Roland; Kaminsky, Ronald; Mäser, Pascal; Sigel, Erwin (2010). Monepantel allosterically activates DEG-3/DES-2 channels of the gastrointestinal nematode Haemonchus contortus. Molecular pharmacology, 78(5), pp. 895-902. Bethesda, Md.: American Society for Pharmacology and Experimental Therapeutics 10.1124/mol.110.066498

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Monepantel is the first drug of a new family of anthelmintics, the amino acetonitrile derivatives (AAD), presently used to treat ruminants infected with gastrointestinal nematodes such as Haemonchus contortus. Monepantel shows an excellent tolerability in mammals and is active against multidrug-resistant parasites, indicating that its molecular target is absent or inaccessible in the host and is different from those of the classic anthelmintics. Genetic approaches with mutant nematodes have suggested acetylcholine receptors of the DEG-3 subfamily as the targets of AADs, an enigmatic clade of ligand-gated ion channels that is specific to nematodes and does not occur in mammals. Here we demonstrate direct interaction of monepantel, its major active metabolite monepantel sulfone, and other AADs with potential targets of the DEG-3 subfamily of acetylcholine receptors. H. contortus DEG-3/DES-2 receptors were functionally expressed in Xenopus laevis oocytes and were found to be preferentially activated by choline, to permeate monovalent cations, and to a smaller extent, calcium ions. Although monepantel and monepantel sulfone did not activate the channels by themselves, they substantially enhanced the late currents after activation of the channels with choline, indicating that these AADs are type II positive allosteric modulators of H. contortus DEG-3/DES-2 channels. It is noteworthy that the R-enantiomer of monepantel, which is inactive as an anthelmintic, inhibited the late currents after stimulation of H. contortus DEG-3/DES-2 receptors with choline. In summary, we present the first direct evidence for interaction of AADs with DEG-3-type acetylcholine receptors and discuss these findings in the context of anthelmintic action of AADs.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine
08 Faculty of Science > Department of Biology > Institute of Cell Biology

UniBE Contributor:

Baur, Roland; Mäser, Pascal and Sigel, Erwin

ISSN:

0026-895X

Publisher:

American Society for Pharmacology and Experimental Therapeutics

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:12

Last Modified:

06 Dec 2013 13:22

Publisher DOI:

10.1124/mol.110.066498

PubMed ID:

20679419

Web of Science ID:

000283148700012

URI:

https://boris.unibe.ch/id/eprint/2427 (FactScience: 204925)

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