The neurotransmitter and neuromodulator serotonin (5-HT) functions by binding either to metabotropic G-protein-coupled receptors (for example, 5-HT1, 5-HT2, 5-HT4 to 5-HT7), which mediate ‘slow’ modulatory responses through numerous second messenger pathways1, or to the ionotropic 5-HT3 receptor, a non-selective cation channel that mediates ‘fast’ membrane depolarizations2. Here we report that the gene mod-1 (for modulation of locomotion defective) from the nematode Caenorhabditis elegans encodes a new type of ionotropic 5-HT receptor, a 5-HT-gated chloride channel. The predicted MOD-1 protein is similar to members of the nicotinic acetylcholine receptor family of ligand-gated ion channels, in particular to GABA (γ-aminobutyric acid)- and glycine-gated chloride channels. The MOD-1 channel has distinctive ion selectivity and pharmacological properties. The reversal potential of the 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-specific antagonists but is inhibited by the metabotropic 5-HT receptor antagonists mianserin and methiothepin. mod-1 mutant animals are defective in a 5-HT-mediated experience-dependent behaviour3 and are resistant to exogenous 5-HT, confirming that MOD-1 functions as a 5-HT receptor in vivo.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Martin, G. R., Eglen, R. M., Hamblin, M. W., Hoyer, D. & Yocca, F. The structure and signalling properties of 5-HT receptors: an endless diversity? Trends Pharmacol. Sci. 19, 2–4 (1998 ).
Maricq, A. V., Peterson, A. S., Brake, A. J., Myers, R. M. & Julius, D. Primary structure and functional expression of the 5HT3 receptor, a serotonin-gated ion channel. Science 254, 432–437 (1991).
Sawin, E. R., Ranganathan, R. & Horvitz, H. R. C. elegans locomotory rate is modulated by the environment through a dopaminergic pathway and by experience through a serotonergic pathway. Neuron 26, 619– 631 (2000).
Horvitz, H. R., Chalfie, M., Trent, C., Sulston, J. E. & Evans, P. D. Serotonin and octopamine in the nematode Caenorhabditis elegans. Science 216, 1012– 1014 (1982).
The C. elegans Sequencing Consortium. Genome sequence of the nematode C. elegans: a platform for investigating biology. Science 282, 2012– 2018 (1998).
Krause, M. & Hirsh, D. A trans-spliced leader sequence on actin mRNA in C. elegans. Cell 49, 753–761 (1987).
Liu, L. X. et al. High-throughput isolation of Caenorhabditis elegans deletion mutants. Genome Res. 9, 859– 867 (1999).
Jansen, G., Hazendonk, E., Thijssen, K. L. & Plasterk, R. H. Reverse genetics by chemical mutagenesis in Caenorhabditis elegans. Nature Genet. 17, 119– 121 (1997).
Sumikawa, K. & Gehle, V. M. Assembly of mutant subunits of the nicotinic acetylcholine receptor lacking the conserved disulfide loop structure. J. Biol. Chem. 267, 6286– 6290 (1992).
Karlin, A. & Akabas, M. H. Toward a structural basis for the function of nicotinic acetylcholine receptors and their cousins. Neuron 15, 1231–1244 ( 1995).
Cooper, J. R., Bloom, F. E. & Roth, R. H. The Biochemical Basis of Neuropharmacology (Oxford Univ. Press, New York, 1996).
Hardie, R. C. A histamine-activated chloride channel involved in neurotransmission at a photoreceptor synapse. Nature 339, 704– 706 (1989).
McClintock, T. S. & Ache, B. W. Histamine directly gates a chloride channel in lobster olfactory receptor neurons. Proc. Natl Acad. Sci. USA 86, 8137– 8141 (1989).
Cully, D. F. et al. Cloning of an avermectin-sensitive glutamate-gated chloride channel from Caenorhabditis elegans. Nature 371, 707–711 (1994).
Adelsberger, H., Lepier, A. & Dudel, J. Activation of rat recombinant α1β 2γ2S GABAA receptor by the insecticide ivermectin. Eur. J. Pharmacol. 394, 163– 170 (2000).
Krause, R. M. et al. Ivermectin: a positive allosteric effector of the α7 neuronal nicotinic acetylcholine receptor. Mol. Pharmacol. 53, 283–294 (1998).
Davies, P. A. et al. The 5-HT3B subunit is a major determinant of serotonin-receptor function. Nature 397, 359– 363 (1999).
Downie, D. L. et al. Pharmacological characterization of the apparent splice variants of the murine 5-HT3 R-A subunit expressed in Xenopus laevis oocytes. Neuropharmacology 33, 473– 482 (1994).
Aizenberg, D. et al. Mianserin, a 5-HT2a/2c and alpha 2 antagonist, in the treatment of sexual dysfunction induced by serotonin reuptake inhibitors. Clin. Neuropharmacol. 20, 210–214 (1997).
Granas, C. & Larhammar, D. Identification of an amino acid residue important for binding of methiothepin and sumatriptan to the human 5-HT(1B) receptor. Eur. J. Pharmacol. 380, 171–181 (1999).
Weber, W. Ion currents of Xenopus laevis oocytes: state of the art. Biochim. Biophys. Acta. 1421, 213– 233 (1999).
Bormann, J., Hamill, O. P. & Sakmann, B. Mechanism of anion permeation through channels gated by glycine and gamma-aminobutyric acid in mouse cultured spinal neurones. J. Physiol. (Lond.) 385, 243– 286 (1987).
Chalfie, M., Tu, Y., Euskirchen, G., Ward, W. W. & Prasher, D. C. Green fluorescent protein as a marker for gene expression. Science 263, 802–805 (1994).
Shaham, S. & Horvitz, H. R. Developing Caenorhabditis elegans neurons may contain both cell-death protecture and killer activities. Genes Dev. 10, 578–591 (1996).
Lessmann, V. & Dietzel, I. D. Development of serotonin-induced ion currents in identified embryonic Retzius cells from the medicinal leech (Hirudo medicinalis). J. Neurosci. 11, 800–809 (1991).
Lessmann, V. & Dietzel, I. D. Two kinetically distinct 5-hydroxytryptamine-activated Cl- conductances at Retzius P-cell synapses of the medicinal leech. J. Neurosci. 15, 1496– 1505 (1995).
Brenner, S. The genetics of Caenorhabditis elegans. Genetics 77, 71–94 (1974).
Mello, C. C., Kramer, J. M., Stinchcomb, D. & Ambros, V. Efficient gene transfer in C. elegans: extrachromosomal maintenance and integration of transforming sequences. EMBO J. 10, 3959–3970 (1991).
Morrill, J. A. & Cannon, S. C. Effects of mutations causing hypokalaemic periodic paralysis on the skeletal muscle L-type Ca2+ channel expressed in Xenopus laevis oocytes. J. Physiol. (Lond.) 520, 321–336 (1999).
Hayward, L. J., Brown, R. H. Jr & Cannon, S. C. Inactivation defects caused by myotonia-associated mutations in the sodium channel III-IV linker. J. Gen. Physiol. 107, 559–576 ( 1996).
We thank N. Buttner, D. Omura and P. Reddien for suggestions concerning this manuscript; G. Moulder and R. Barstead for help in isolating the mod-1(ok103) allele; L. Liu and C. Johnson for sharing the mod-1(nr2043) allele before publication; and D. Julius for the 5-HT3a cDNA clone. This work was supported by a grant from the United States Public Health Service (H.R.H.). R.R. is supported by a Howard Hughes Medical Institute predoctoral fellowship. H.R.H. is an Investigator of the Howard Hughes Medical Institute.
About this article
Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology (2019)
Neuroscience Research (2019)
Analysis of classical neurotransmitter markers in tapeworms: Evidence for extensive loss of neurotransmitter pathways
International Journal for Parasitology (2018)
The Journal of Experimental Biology (2018)