MOD-1 is a serotonin-gated chloride channel that modulates locomotory behaviour in C. elegans

The neurotransmitter and neuromodulator serotonin (5-HT) functions by bindi ng either to metabotropic G-protein-coupled receptors (for example, 5-HT1, 5-HT2, 5-HT4 to 5-HT7), which mediate 'slow' modulatory responses through n umerous second messenger pathways(1), or to the ionotropic 5-HT3 receptor, a non-selective cation channel that mediates 'fast' membrane depolarization s(2). Here we report that the gene mod-1 (for modulation of locomotion defe ctive) from the nematode Caenorhabditis elegans encodes a new type of ionot ropic 5-HT receptor, a 5-HT-gated chloride channel. The predicted MOD-1 pro tein is similar to members of the nicotinic acetylcholine receptor family o f ligand-gated ion channels, in particular to GABA (gamma -aminobutyric aci d)- and glycine-gated chloride channels. The MOD-1 channel has distinctive ion selectivity and pharmacological properties. The reversal potential of t he MOD-1 channel is dependent on the concentration of chloride ions but not of cations. The MOD-1 channel is not blocked by calcium ions or 5-HT3a-spe cific antagonists but is inhibited by the metabotropic 5-HT receptor antago nists mianserin and methiothepin. mod-1 mutant animals are defective in a 5 -HT-mediated experience-dependent behaviour(3) and are resistant to exogeno us 5-HT, confirming that MOD-1 functions as a 5-HT receptor in vivo.