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

@article{Wolstenholme2005GlutamategatedCC,
  title={Glutamate-gated chloride channels and the mode of action of the avermectin/milbemycin anthelmintics},
  author={Adrian J. Wolstenholme and Adrian T. Rogers},
  journal={Parasitology},
  year={2005},
  volume={131},
  pages={S85 - S95}
}
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… 
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The G36’A mutation in the third transmembrane domain, which was previously thought to hinder access of IVM to its binding site, was found to decrease the duration of active periods and increase receptor desensitisation rates, providing new insights into the activation and modulatory mechanisms of the H. contortus GluClRs and provide a mechanistic framework upon which the actions of drugs can be reliably interpreted.
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Possible reasons for resistance to the macrocyclic lactone family of anthelmintics, and its consequences for the development of molecular tests for resistance, are explored.
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TLDR
Molecular modeling studies suggested that the GluCl subunits have a fold similar to that of other Cys-loop ligand-gated ion channels and that amino acid 256 was unlikely to play a direct role in ligand binding but may be involved in mediating the allosteric properties of the receptor.
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TLDR
Using voltage-clamp fluorometry, this technique has demonstrated that ivermectin induces a global conformational change that propagates from the transmembrane domain to the neurotransmitter binding site, thus suggesting a mechanism by which iverMectin potentiates neurotransmitter-gated currents.
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TLDR
It is demonstrated that IVM potentiates inhibitory input by inducing a tonic current that plateaus over 15 minutes and by enhancing post-synaptic current peak amplitude and decay times, and it is discovered functional groups of IVM that contribute to tuning its potency at different isoforms.
1 Ligand-Gated Ion Channels as Targets for Anthelmintic Drugs : Past , Current , and Future Perspectives
TLDR
LGIC targets for the current anthelmintics of commercial importance are described and the potential impact of that knowledge on screening for new compounds is discussed and new developments in the understanding of LGIC chaperones and automated screening technologies may hold promise for target validation and chemical library screening on whole organisms or ex vivo preparations.
Ligand-Gated Ion Channels as Targets for Anthelmintic Drugs: Past, Current, and Future Perspectives
TLDR
LGIC targets for the current anthelmintics of commercial importance are described and the potential impact of that knowledge on screening for new compounds is discussed and new developments in the understanding of LGIC chaperones and automated screening technologies may hold promise for target validation and chemical library screening on whole organisms or ex vivo preparations.
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TLDR
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