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Novel animal-health drug targets from ligand-gated chloride channels

Key Points

  • Ligand-gated ion channels are targets of the most commonly used veterinary antiparasitic drugs (parasiticides).

  • The sequencing of the complete genomes of the genetic model organisms Caenorhabditis elegans (worm) and Drosophila melanogaster (fly) has allowed the identification of new ligand-gated anion channels, some of which are known only from invertebrates.

  • These newly discovered invertebrate-specific ion channels provide possible new targets for developing a new generation of animal-health drugs.

  • Studies on channel mutations have added to our understanding of ligand-gated-ion-channel function, drug interactions and drug-resistance mechanisms.

Abstract

The world's three best-selling veterinary antiparasitic drugs ('parasiticides') act on ligand-gated ion channels. The sequencing of the complete genomes of the invertebrate genetic model organisms Caenorhabditis elegans and Drosophila melanogaster has led to the recent cloning of new subunits of 5-hydroxytryptamine-gated and histamine-gated chloride channels. Together with l-glutamate-gated chloride channels, which are important targets of known parasiticides, and acetylcholine-gated chloride channels, these new classes of ligand-gated chloride channels, which are known only from invertebrates, add to our understanding of inhibitory neural signalling. They could offer the prospect of being targets for a new generation of selective drugs to control nematode and insect parasites.

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Figure 1: Structures of compounds that are active on ligand-gated chloride channels.
Figure 2: Ligand-gated ion channels (LGICs).
Figure 3: Physiological roles of ligand-gated chloride channels.

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Acknowledgements

The authors are indebted to their colleagues in the MRC Functional Genetics Unit for helpful comments on the manuscript. This work was supported by the Medical Research Council of the United Kingdom.

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Correspondence to David B. Sattelle.

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DATABASES

FlyBase

DmHisCl1

DmHisCl2

RDL receptor

GenBank

α7 nAChR

LocusLink

GABAA receptor

GABAA-receptor α1-subunit

glycine-receptor α1-subunit

glycine-receptor β-subunit

5-HT3 receptors

Medscape DrugInfo

ivermectin

WormBase

ACR-8

AVR-14

AVR-15

dyf

GLC-3

mod-1

unc-7

unc-9

unc-49

FURTHER INFORMATION

GeneDoc

National Center for Biotechnology Information

Glossary

PARASITICIDE

An antiparasitic drug. A chemical that controls parasites, such as worms, ticks, fleas and mites.

IONOTROPIC RECEPTOR

A ligand-gated ion channel that is composed of several subunits. Activation by the ligand (for example, a neurotransmitter) transiently opens an integral ion channel. The 'Cys-loop'-receptor superfamily is a major class of ionotropic receptors.

ALTERNATIVE SPLICING

Different products can be generated from a single gene by, for example, combining alternative forms of particular exons.

RNA EDITING

A mechanism in cells that can generate new functional transcripts from existing ones, which results in the replacement at specific sites of one amino acid by another.

HETEROMERIC RECEPTOR

A type of oligomeric receptor that is composed of at least two subunit isoforms.

HOMOMERIC RECEPTOR

A type of oligomeric receptor that is composed of identical subunits.

DESENSITIZATION

The mechanism by which a ligand becomes less effective at activating a receptor during a prolonged application.

SITE-DIRECTED MUTAGENESIS

An in vitro mechanism that introduces mutations (base-pair changes) at a specific site in the DNA sequence.

CHEMISTRY-TO-GENE SCREEN

After mutagenesis of C. elegans, mutants are screened for resistance to a particular chemical, and the resulting mutations are mapped and identified (useful for identifying drug targets).

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Raymond, V., Sattelle, D. Novel animal-health drug targets from ligand-gated chloride channels. Nat Rev Drug Discov 1, 427–436 (2002). https://doi.org/10.1038/nrd821

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