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

A J Wolstenholme, A T Rogers

Research output: Contribution to journalArticlepeer-review

237 Citations (Scopus)

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 implicatcd 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.
Original languageEnglish
Pages (from-to)S85-S95
JournalParasitology
Volume131
DOIs
Publication statusPublished - 2005

Fingerprint Dive into the research topics of 'Glutamate-gated chloride channels and the mode of action of the avermectin/milbemycin anthelmintics'. Together they form a unique fingerprint.

Cite this