Glutamate-gated chloride channels (GluCl) are a class of ligand-gated ion channel receptor found only in invertebrates, including nematodes. They are the targets of the avermectin/milbemycin anthelmintics, including ivermectin. Four C. elegans genes (
glc-1,
glc-2,
avr-14 [which has also been called
gbr-2] and
avr-15) have been demonstrated to encode GluCl subunits. A further predicted C. elegans gene, ZC317.3, has high sequence identity to the GluCl genes. We have cloned and expressed the gene product and shown that it does indeed encode a further GluCl subunit. We have therefore named the gene
glc-3. Expression of
glc-3 cRNA in Xenopus oocytes resulted in the formation of homo-oligomeric L-glutamate-gated chloride channels with robust and rapidly desensitising currents, an EC50 of 1.9mM and a Hill coefficient of 1.5. GABA, glycine, histamine and NMDA all failed to activate the GLC-3 homo-oligomer at concentrations of 1mM. Ivermectin directly and irreversibly activated the L-glutamate-gated channels with an EC50 of 0.4microM. The channels were selective for chloride ions, as shown by a shift in the reversal potential for L-glutamate-gated currents after the reduction of external Cl- from 107.6mM to 62.5mM. These properties are similar to those of other GluCl alpha subunits encoded by the
avr-14 and
avr-15 genes. Picrotoxinin, a non-competitive antagonist of most other native and recombinant GluCl, failed to inhibit L-glutamate agonist responses at concentrations up to 1mM. However, the polycyclic dinitrile, 3,3-bis-trifluoromethyl-bicyclo[2,2,1]heptane-2,2-dicarbonitrile (BIDN), completely blocked L-glutamate-induced chloride currents recorded from oocytes expressing GLC-3 with an IC50 of 0.2microM. The phenylpyrazole insecticide, fipronil, reversibly inhibited L-glutamate-gated currents recorded from the GLC-3 receptor with an IC50 of 11.5microM. BIDN and fipronil have previously been reported to be specific blockers of GABA-gated channels. This antagonist pharmacology differs from that reported for the other GluCl alpha subunits.