Biogenic amines commonly function as neuromodulators by activating metabotropic G protein-coupled receptors. In vertebrates, the biogenic amine serotonin (5-HT) also functions as a fast-acting excitatory neurotransmitter by activating the ionotropic 5-HT3 receptor, a non-selective cation channel. In C. elegans, 5-HT may function as a fast-acting inhibitory neurotransmitter through MOD-1, a 5-HT-gated chloride channel (Ranganathan, Cannon, and Horvitz, Nature 408: 470-475, 2000).To determine whether there are other MOD-1-like receptors in C. elegans, we searched the C. elegans genome for sequences similar to the
mod-1 coding sequence and found 26 uncharacterized genes predicted to encode ligand-gated chloride channels. We are expressing each of these genes in Xenopus oocytes and testing them for amine receptor activity. So far we have identified three novel ionotropic receptors gated by biogenic amines. One of these receptors, encoded by the gene T21F2.1, is activated most potently by dopamine. Another, encoded by Y113G7A.5, is most potently activated by tyramine. A receptor encoded by the gene T24D8.1 is activated by high concentrations of 5-HT and not by other tested amines. Ion-replacement studies suggest that, like MOD-1, these channels selectively pass chloride ions.To understand how these receptors function in vivo, we have isolated deletion mutants in these three genes and are characterizing their behaviors. Mutants carrying a deletion in the gene Y113G7A.5 have a Sho phenotype (Suppression of head oscillations-defective), suggesting that this ion channel functions in a tyraminergic signaling pathway in vivo. Mutants carrying a deletion in the gene T21F2.1 have a defect in basal slowing, a dopamine-dependent modulation of locomotion, suggesting that this ion channel functions as a dopamine receptor in vivo. T21F2.1 and Y113G7A.5 are, to our knowledge, the first identified ionotropic receptors for tyramine and dopamine. Our studies and those of MOD-1 suggest a broad role for ligand-gated chloride channels in aminergic signaling in C. elegans.