title: avr-15 encodes a chloride channel subunit that mediates inhibitory glutamatergic neurotransmission and ivermectin sensitivity in Caenorhabditis elegans.
abstract: Ivermectin is a widely used anthelmintic drug whose nematocidal mechanism is incompletely understood. We have used Caenorhabditis elegans as a model system to understand ivermectin's effects. We found that the M3 neurons of the C.elegans pharynx form fast inhibitory glutamatergic neuromuscular synapses. avr-15, a gene that confers ivermectin sensitivity on worms, is necessary postsynaptically for a functional M3 synapse and for the hyperpolarizing effect of glutamate on pharyngeal muscle. avr-15 encodes two alternatively spliced channel subunits that share ligand binding and transmembrane domains and are members of the family of glutamate-gated chloride channel subunits. An avr-15-encoded subunit forms a homomeric channel that is ivermectin-sensitive and glutamate-gated. These results indicate that: (i) an ivermectin-sensitive chloride channel mediates fast inhibitory glutamatergic neuromuscular transmission; and (ii) a nematocidal property of ivermectin derives from its activity as an agonist of glutamate-gated chloride channels in essential excitable cells such as those of the pharynx.
authors.affiliation: Department of Molecular Biology and Oncology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, TX 75235-9148, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Dent
authors.forename: M W
authors.initials: MW
authors.lastname: Davis
authors.forename: L
authors.initials: L
authors.lastname: Avery
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D000969:Antinematodal Agents / Q000494:pharmacology*; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D018118:Chloride Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D007478:Iontophoresis; D007559:Ivermectin / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009126:Muscle Relaxation / Q000187:drug effects; D010614:Pharynx / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*
chemical_list: D000969:Antinematodal Agents; D018118:Chloride Channels; D018698:Glutamic Acid; D007559:Ivermectin