AVR-15 ENCODES A CHLORIDE CHANNEL SUBUNIT THAT MEDIATES INHIBITORY GLUTAMATERGIC NEUROTRANSMISSION AND IVERMECTIN SENSITIVITY IN CAENORHABDITIS-ELEGANS

Ivermectin is a widely used anthelmintic drug whose nematocidal mechan ism 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 sensit ivity on worms, is necessary postsynaptically for a functional M3 syna pse and for the hyperpolarizing effect of glutamate on pharyngeal musc le, avr-15 encodes two alternatively spliced channel subunits that sha re ligand binding and transmembrane domains and are members of the fam ily of glutamate-gated chloride channel subunits, An avr-15-encoded su bunit forms a homomeric channel that is ivermectin-sensitive and gluta mate-gated, These results indicate that: (i) an ivermectin-sensitive c hloride channel mediates fast inhibitory glutamatergic neuromuscular t ransmission; and (ii) a nematocidal property of ivermectin derives fro m its activity as an agonist of glutamate-gated chloride channels in e ssential excitable cells such as those of the pharynx.