avr-15 encodes a chloride channel subunit that mediates inhibitory glutamatergic neurotransmission and ivermectin sensitivity in Caenorhabditis elegans

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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.