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Glutamate-gated chloride channels and the mode of action of the avermectin/milbemycin anthelmintics

Published online by Cambridge University Press:  29 March 2006

A. J. WOLSTENHOLME  and
A. T. ROGERS
A. J. WOLSTENHOLME
Affiliation:
Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK.
A. T. ROGERS
Affiliation:
Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK.
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Abstract

The macrocyclic lactones are the biggest selling and arguably most effective anthelmintics currently available. They are good substrates for the P-glycoproteins, which might explain their selective toxicity for parasites over their vertebrate hosts. Changes in the expression of these pumps have been implicated in resistance to the macrocyclic lactones, but it is clear that they exert their anthelmintic effects by binding to glutamate-gated chloride channels expressed on nematode neurones and pharyngeal muscle cells. This effect is quite distinct from the channel opening induced by glutamate, the endogenous transmitter acting at these receptors, which produces rapidly opening and desensitising channels. Ivermectin-activated channels open very slowly but essentially irreversibly, leading to a very long-lasting hyperpolarisation or depolarisation of the neurone or muscle cell and therefore blocking further function. Molecular and genetic studies have shown that there are multiple GluCl isoforms in both free-living and parasitic nematodes: the exact genetic make-up and functions of the GluCl may vary between species. The known expression patterns of the GluCl explain most of the observed biological effects of treatment with the macrocyclic lactones, though the reason for the long-lasting inhibition of larval production in filarial species is still poorly understood.

Keywords

IvermectinCaenorhabditis elegansHaemonchus contortusFilariaionotropic receptorchemotherapy
Type
Research Article
Information
Parasitology , Volume 131 , Supplement S1: Parasite neuromusculature and its utility as a drug target , October 2005 , pp. S85 - S95
Copyright
2005 Cambridge University Press

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