GLC‐3: a novel fipronil and BIDN‐sensitive, but picrotoxinin‐insensitive, L‐glutamate‐gated chloride channel subunit from Caenorhabditis elegans

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Abstract
We report the cloning and expression of a novel Caenorhabditis elegans polypeptide, GLC‐3, with high sequence identity to previously cloned L‐glutamate‐gated chloride channel subunits from nematodes and insects. Expression of glc‐3 cRNA in Xenopus oocytes resulted in the formation of homo‐oligomeric L‐glutamate‐gated chloride channels with robust and rapidly desensitizing currents, an EC50 of 1.9±0.03 mM and a Hill coefficient of 1.5±0.1. GABA, glycine, histamine and NMDA all failed to activate the GLC‐3 homo‐oligomer at concentrations of 1 mM. The anthelminthic, ivermectin, directly and irreversibly activated the L‐glutamate‐gated channel with an EC50 of 0.4±0.02 μM. The GLC‐3 channels were selective for chloride ions, as shown by the shift in the reversal potential for L‐glutamate‐gated currents after the reduction of external Cl− from 107.6 to 62.5 mM. Picrotoxinin failed to inhibit L‐glutamate agonist responses at concentrations up to 1 mM. 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 0.2±0.07 μM. The phenylpyrazole insecticide, fipronil, reversibly inhibited L‐glutamate‐gated currents recorded from the GLC‐3 receptor with an IC50 of 11.5±0.11 μM. In this study, we detail the unusual antagonist pharmacology of a new GluCl subunit from C. elegans. Unlike all other native and recombinant nematode GluCl reported to date, the GLC‐3 receptor is insensitive to picrotoxinin, but is sensitive to two other channel blockers, BIDN and fipronil. Further study of this receptor may provide insights into the molecular basis of non‐competitive antagonism by these compounds. British Journal of Pharmacology (2001) 132, 1247–1254; doi:10.1038/sj.bjp.0703937

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