Glutamate-gated Cl- channels in Caenorhabditis elegans and parasitic nematodes.

Excitatory ionotropic and metabotropic glutamate receptors are found throughout the animal kingdom, but inhibitory ionotropic glutamate receptors seem to be confined to invertebrates (reviewed in [l]). Molecular studies on all invertebrate receptors have lagged far behind those of their mammalian counterparts, but recently interest in the glutamate-gated C1channels (Glu-Cl) has been greatly stimulated by the discovery that, at least in Caenorhabditis elegans, these molecules act as the receptor for, and probable site of action of, the avermectins, a family of potent anthelminthics, insecticides and acaricides. Electrophysiological studies on Xenopus oocytes injected with total C. elegans mRNA showed that ivermectin (22,23-dihydroavermectin B 1) was able to potentiate glutamate-induced C1currents at nanomolar concentrations [Z], and allowed the expression cloning of two cDNAs encoding subunits of the receptor [3], designated Glu-Cl a (now referred to as a l ) and Glu-Cl P: we also cloned the P-subunit using reverse transcriptase PCR techniques [4]. The sequences of these subunits revealed that the general structure of this receptor is identical with the mammalian y-aminobutyric acid type A (GABA,) and glycine receptors, with a long N-terminal extracellular region and four putative transmembrane domains. No similarity to the mammalian excitatory glutamate receptor sequences was detected. When expressed in Xenopus oocytes, the a 1-subunit forms ivermectin-gated C1channels, the P-subunit forms Glu-Cl and, on co-expression, an ivermectinpotentiated Glu-C1 is formed [3]. Later experiments demonstrated that the a 1-subunit also possessed a glutamate-binding site, but that binding was not coupled to the opening of the C1channel [S]. These results are consistent with physiological and pharmacological data that suggest that the inhibitory glutamate receptors most closely resemble GABA, receptors. With the exception of ibotenic acid, glutamatergic agonists generally have no effect at this site, although they are picrotoxin-sensitive [2,3,6]. More recently J. Dent and L. Avery (personal