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


Reference:

Wolstenholme, A. J. and Rogers, A. T., 2005. Glutamate-gated chloride channels and the mode of action of the avermectin/milbemycin anthelmintics. Parasitology, 131, S85-S95.

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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 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.

Details

Item Type Articles
CreatorsWolstenholme, A. J.and Rogers, A. T.
DOI10.1017/s0031182005008218
DepartmentsFaculty of Science > Biology & Biochemistry
RefereedYes
StatusPublished
ID Code3745
Additional InformationID number: ISI:000237277300007

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