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Evidence for a Diverse Cys-Loop Ligand-Gated Ion Channel Superfamily in Early Bilateria

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Abstract

The genome sequences of Caenorhabditis elegans and Drosophila melanogaster reveal a diversity of cysteine-loop ligand-gated ion channels (Cys-loop LGICs) not found in vertebrates. To better understand the evolution of this gene superfamily, I compared all Cys-loop LGICs from rat, the primitive chordate Ciona intestinalis, Drosophila, and C. elegans. There are two clades of GABA receptor subunits that include both verterbate and invertebrate orthologues. In addition, I identified nine clades of anion channel subunits found only in invertebrates, including three that are specific to C. elegans and two found only in Drosophila. One well-defined clade of vertebrate cation channel subunits, the α7 nicotinic acetylcholine receptor subunits (nAChR), includes invertebrate orthologues. There are two clades of invertebrate nAChRs, one of α-type subunits and one of non-α subunits, that are most similar to the two clades of vertebrate neuronal and muscle α and non-α subunits. There is a large group of divergent C. elegans nAChR-like subunits partially resolved into clades but no orthologues of 5HT3-type serotonin receptors in the invertebrates. The topology of the trees suggests that most of the invertebrate-specific Cys-loop LGIC clades were present in the common ancestor of chordates and ecdysozoa. Many of these disappeared from the chordates. Subsequently, selected subunit genes expanded to form large subfamilies.

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References

  • Abascal F, Zardoya R, Posada D (2005) ProtTest: selection of best–fit models of protein evolution. Bioinformatics 21:2104–2105

    Article  CAS  PubMed  Google Scholar 

  • Adams MD, Celniker SE, Holt RA, et al. (2000) The genome sequence of Drosophila melanogaster. Science 287:2185–2195

    Article  PubMed  Google Scholar 

  • Aguinaldo AMA, Turbeville JM, Linford LS, Rivera MC, Garey JR, Raff RA, Lake JA (1997) Evidence for a clade of nematodes, arthropods and other molting animals. Nature 387:489–493

    Article  CAS  PubMed  Google Scholar 

  • Aronstein K, Auld V, Ffrench-Constant R (1996) Distribution of two GABA receptor-like subunits in the Drosophila CNS. Invertebr Neurosci 2:115–120

    Article  CAS  Google Scholar 

  • Ballivet M, Alliod C, Bertrand S, Bertrand D (1996) Nicotinic acetylcholine receptors in the nematode Caenorhabditis elegans. J Mol Biol 256:261–269

    Article  Google Scholar 

  • Bamber BA, Beg AA, Twyman RE, Jorgensen EM (1999) The Caenorhabditis elegans unc-49 locus encodes multiple subunits of a heteromultimeric GABA receptor. J Neurosci 19:5348–5359

    CAS  PubMed  Google Scholar 

  • Beg AA, Jorgensen EM (2003) EXP-1 is an excitatory GABA-gated cation channel. Nat Neurosci 6:1145–1152

    Article  CAS  PubMed  Google Scholar 

  • Brejc K, van Dijk WJ, Klaassen RV, Schuurmans M, van Der Oost J, Smit AB, Sixma TK (2001) Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature 411:269–276

    Article  CAS  PubMed  Google Scholar 

  • Brotz TM, Gundelfinger ED, Borst A (2001) Cholinergic and GABAergic pathways in fly motion vision. BMC Neuroscience, 2

  • Buck L, Axel R (1991) A novel multigene family may encode odorant receptors: a molecular basis for odor recognition. Cell 65:175–187

    Article  CAS  PubMed  Google Scholar 

  • Cockroft VB, Osguthorpe EA, Barnard EA, Friday AE, Lunt GG (1992) Ligand-gated ion channels. Mol Neurobiol 4:129–169

    Google Scholar 

  • Consortium, The C elegans Genome (1998) Genome sequence of the nematode C elegans: a platform for investigating biology. The C elegans Sequencing Consortium. Science 282:2012–2018

    Article  Google Scholar 

  • Culetto E, Baylis HA, Richmond JE, Jones AK, Fleming JT, Squire MD, Lewis JA, Sattelle DB (2004) The Caenorhabditis elegans unc-63 gene encodes a levamisole-sensitive nicotinic acetylcholine receptor alpha subunit. J Biol Chem 279:42476–42483

    Article  CAS  PubMed  Google Scholar 

  • Cully DF, Vassilatis DK, Liu KK, Paress PS, Van der Ploeg LH, Schaeffer JM, Arena JP (1994) Cloning of an avermectin-sensitive glutamate-gated chloride channel from Caenorhabditis elegans. Nature 371:707–711

    Article  CAS  PubMed  Google Scholar 

  • Cully DF, Paress PS, Liu KK, Schaeffer JM, Arena JP (1996) Identification of a Drosophila melanogaster glutamate-gated chloride channel sensitive to the antiparasitic agent avermectin. J Biol Chem 271:20187–20191

    Article  CAS  PubMed  Google Scholar 

  • Daniels SB, Peterson KR, Strausbaugh LD, Kidwell MG, Chovnick A (1990) Evidence for horizontal transmission of the P transposable element between Drosophila species. Genetics 124:339–355

    CAS  PubMed  Google Scholar 

  • Davies PA, Wang W, Hales TG, Kirkness EF (2003) A novel class of ligand-gated ion channel is activated by Zn2+. J Biol Chem 278:712–717

    Article  CAS  PubMed  Google Scholar 

  • Dehal P, Satou Y, Campbell RK, et al. (2002) The draft genome of Ciona intestinalis: insights into chordate and vertebrate origins. Science 298:2157–2167

    Article  CAS  PubMed  Google Scholar 

  • Dent JA, Davis MW, Avery L (1997) avr-15 encodes a chloride channel subunit that mediates inhibitory glutamatergic neurotransmission and ivermectin sensitivity in Caenorhabditis elegans. EMBO J 16:5867–5879

    Article  CAS  PubMed  Google Scholar 

  • Edgar RC (2004) MUSCLE: multiple sequence alignment with high accuracy and high throughput. Nucleic Acids Res 32:1792–1797

    Article  CAS  PubMed  Google Scholar 

  • Felsenstein J (1973) Maximum-likelihood and minimum steps methods for estimating evolutionary trees from data on discrete characters. Syst Zool 27:27–33

    Google Scholar 

  • Feng XP, Hayashi J, Beech RN, Prichard RK (2002) Study of the nematode putative GABA type-A receptor subunits: evidence for modulation by ivermectin. J Neurochem 83:870–878

    Article  CAS  PubMed  Google Scholar 

  • Fitch WM (1971) Towards defining the course of evolution: minimum change for a specific tree topology. Syst Zool 20:406–416

    Google Scholar 

  • Fleming JT, Squire MD, Barnes TM, Tornoe C, Matsuda K, Ahnn J, Fire A, Sulston JE, Barnard EA, Sattelle DB, Lewis JA (1997) Caenorhabditis elegans levamisole resistance genes lev-1, unc-29, and unc-38 encode functional nicotinic acetylcholine receptor subunits. J Neurosci 17:5843–5857

    CAS  PubMed  Google Scholar 

  • Galzi JL, Devillers-Thiery A, Hussy N, Bertrand S, Changeux JP,Bertrand D (1992) Mutations in the channel domain of a neuronal nicotinic receptor convert ion selectivity from cationic to anionic. Nature 359:500–505

    Article  CAS  PubMed  Google Scholar 

  • Gelbart WM, Crosby M, Matthews B, Rindone WP, Chillemi J, Russo Twombly S, Emmert D, Ashburner M, Drysdale RA, Whitfield E, Millburn GH, de Grey A, Kaufman T, Matthews K, Gilbert D, Strelets V, Tolstoshev C (1997) FlyBase: a Drosophila database. The FlyBase consortium. Nucleic Acids Res 25:63–66

    Article  CAS  PubMed  Google Scholar 

  • Gengs C, Leung H-T, Skingsley DR, Iovchev MI, Yin Z, Semenov EP, Burg MG, Hardie RC, Pak WL (2002) The target of Drosophila photoreceptors synaptic transmission is a histamine-gated chloride channel encoded by ort (hclA). J Biol Chem 277:42113–42120

    Article  CAS  PubMed  Google Scholar 

  • Gisselmann G, Pusch H, Hovemann BT, Hatt H (2002) Two cDNAs coding for histamine-gated ion channels in D melanogaster. Nat Neurosci 5:11–12

    Article  CAS  PubMed  Google Scholar 

  • Gisselmann G, Plonka J, Pusch H, Hatt H (2004) Drosophila melanogaster GRD and LCCH3 subunits form heteromultimeric GABA-gated cation channels. Br J Pharmacol 142:409–413

    Article  CAS  PubMed  Google Scholar 

  • Guindon S, Olivier G (2003) A simple , fast, and accurate algorithm to estimate large phylogenies by maximum likelihood. Syst Biol 52:696–704

    Article  PubMed  Google Scholar 

  • Hille B (1992) Ionic channels of excitable membranes. Sinauer Associates, Sunderland, MA

    Google Scholar 

  • Horoszok L, Raymond V, Sattelle DB, Wolstenholme AJ (2001) GLC-3: a novel fipronil and BIDN-sensitive, but picrotoxinin-insensitive, L-glutamate-gated chloride channel subunit from Caenorhabditis elegans. Br J Pharmacol 132:1247–1254

    Article  CAS  PubMed  Google Scholar 

  • Hosie AM, Ozoe Y, Koike K, Ohmoto T, Nikaido T, Sattelle DB (1996) Actions of picrodendrin antagonists on dieldrin-sensitive and -resistant Drosophila GABA receptors. Br J Pharmacol 119:1569–1576

    CAS  PubMed  Google Scholar 

  • Jones AK, Sattelle DB (2003) Functional genomics of the nicotinic acetylcholine receptor gene family of the nematode, Caenorhabditis elegans. BioEssays 26:39–49

    Article  CAS  Google Scholar 

  • Jones AK, Grauso M, Sattelle DB (2005) The nicotinic acetylcholine receptor gene family of the malaria mosquito, Anopheles gambiae. Genomics 85:176–187

    Article  CAS  PubMed  Google Scholar 

  • Jordan IK, Matyunina LV, McDonald JF (1999) Evidence for the recent horizontal transfer of long terminal repeat retrotransposon. Proc Natl Acad Sci USA 96:12621–12625

    Article  CAS  PubMed  Google Scholar 

  • Karlin A (2002) Emerging structure of the nicotinic acetylcholine receptors. Nat Rev Neurosci 3:102–114

    Article  CAS  PubMed  Google Scholar 

  • Kolaczkowski B, Thornton JW (2004) Performance of maximum parsimony and likelihood phylogenetics when evolution is hetergeneous. Nature 431:980–984

    Article  CAS  PubMed  Google Scholar 

  • Lansdell SJ, Millar NS (2000) Cloning and heterologous expression of Dalpha4, a Drosophila neuronal nicotinic acetylcholine receptor subunit: identification of an alternative exon influencing the efficiency of subunit assembly. Neuropharmacology 39:2604–2614

    Article  CAS  PubMed  Google Scholar 

  • Le Novere N, Changeux J-P (1995) Molecular evolution of the nicotinic acetylcholine receptor: an example of multigene family in excitable cells. J Mol Evol 40:155–172

    Article  CAS  PubMed  Google Scholar 

  • Le Novere N, Corringer P-J, Changeux J-P (2002) The diversity of subunit composition in nAChRs: evolutionary origins, physiologic and pharmacologic consequences. J Neurobiol 53:447–456

    Article  CAS  PubMed  Google Scholar 

  • Littleton JT, Ganetzky B (2000) Ion channels and synaptic organization: analysis of the Drosophila genome. Neuron 26:35–43

    Article  CAS  PubMed  Google Scholar 

  • McKay JP, Raizen DM, Gottschalk A, Schafer WR, Avery L (2004) eat-2 and eat-18 are required for nicotinic neurotransmission in the Caenorhabditis elegans pharynx. Genetics 166:161–169

    Article  CAS  PubMed  Google Scholar 

  • Mongan NP, Baylis HA, Adcock C, Smith GR, Sansom MS, Sattelle DB (1998) An extensive and diverse gene family of nicotinic acetylcholine receptor alpha subunits in Caenorhabditis elegans. Receptors Channels 6:213–28

    CAS  PubMed  Google Scholar 

  • Mongan NP, Jone AK, Smith GR, Sansom MSP, Sattelle DB (2002) Novel alpha 7-like nicotinic acetylcholine receptor subunits in the nematode Caenorhabditis elegans. Prot Sci 11:1162–1171

    Article  CAS  Google Scholar 

  • Ortells MO, Lunt GG (1995) Evolutionary history of the ligand-gated ion-channel superfamily of receptors. Trends Neurosci 18:121–127

    Article  CAS  PubMed  Google Scholar 

  • Perovic S, Krasko A, Prokic I, Muller IM, Muller WE (1999) Origin of neuronal-like receptors in Metazoa: cloning of a metabotropic glutamate/GABA-like receptor from the marine sponge Geodia cydonium. Cell Tissue Res 296:395–404

    Article  CAS  PubMed  Google Scholar 

  • Peterson KJ, Lyons JB, Nowak KS, Takacs CM, Wargo MJ, McPeek MA (2004) Estimating metazoan divergence times with a molecular clock. Proc Natl Acad Sci USA 101:6536–6541

    Article  CAS  PubMed  Google Scholar 

  • Pierobon P, Minei R, Porcu P, Sogliano C, Tino A, Marino G, Biggio G, Concas A (2004) Putative glycine receptors in Hydra: a biochemical and behavioural study. Eur J Neurosci 14:1659–1666

    Article  Google Scholar 

  • Putrenko I, Zakikhani M, Dent JA (2005) A family of acetylcholine-gated chloride channel subunits in Caenorhabditis elegans. J Biol Chem 280(8):6392–6398

    Article  CAS  PubMed  Google Scholar 

  • Rajendra S, Vandenberg RJ, Pierce KD, Cunningham AM, French PW, Barry PH, Schofield PR (1995) The unique extracellular disulfide loop of the glycine receptor is a principal ligand binding. EMBO J 14:2987–2998

    CAS  PubMed  Google Scholar 

  • Ranganathan R, Cannon SC, Horvitz HR (2000) MOD-1 is a serotonin-gated chloride channel that modulates locomotory behaviour in C. elegans. Nature 408:470–475

    Article  CAS  PubMed  Google Scholar 

  • Richmond JE, Jorgensen EM (1999) One GABA and two acetylcholine receptors function at the C. elegans neuromuscular junction. Nat Neurosci 2:791–797

    Article  CAS  PubMed  Google Scholar 

  • Ruiz-Trillo I, Riutort M, Littlewood TJ, Herniou EA, Baguna J (1999) Acoel flatworms: earliest extant bilaterian metazoans, not members of platyhelminthes. Science 283:1919–1923

    Article  CAS  PubMed  Google Scholar 

  • Saitou N, Nei M (1987) The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol Biol Evol 4:406–425

    CAS  PubMed  Google Scholar 

  • Schulz R, Sawruk E, Mulhardt C, Bertrand S, Baumann A, Phannavong B, Betz H, Bertrand D, Gundelfinger ED, Schmitt B (1998) D alpha3, a new functional alpha subunit of nicotinic acetylcholine receptors from Drosophila. J Neurochem 71:853–862

    Article  CAS  PubMed  Google Scholar 

  • Scott K, Brady R Jr, Cravchik A, Morozov P, Rzhetsky A, Zuker C, Axel R (2001) A chemosensory gene family encoding candidate gustatory and olfactory receptors in Drosophila. Cell 104:661–673

    Article  CAS  PubMed  Google Scholar 

  • Stein L, Sternberg P, Durbin R, Thierry-Mieg J, Spieth J (2001) WormBase: network access to the genome and biology of Caenorhabditis elegans. Nucleic Acids Res 29:82–86

    Article  CAS  PubMed  Google Scholar 

  • Stein LD, Bao Z, Blasiar D, Blumenthal T, Brent MR, Chen N, Chinwalla A, Clarke L, Clee C, Coghlan A, Coulson A, D’Eustachio P, Fitch DHA, Fulton LA, Fulton RE, Griffiths-Jones S, Harris TW, Hillier LD, Kamath R, Kuwabara PE, Mardis ER, Marra MA, Miner TL, Minx P, Mullikin JC, Plumb RW, Rogers J, Schein JE, Sohrmann M, Spieth J, Stajich JE, Wei C, Willey D, Wilson RK, Durbin R, Waterston RH (2003) The genome sequence of Caenorhabditis briggsae: a platform for comparative genomics. PloS Biol 1:166–192

    Article  CAS  Google Scholar 

  • Tasneem A, Lakshminaayan MI, Jakobsson E, Aravind L (2004) Identification of the prokaryotic ligand-gated ion channels and their implications for the mechanisms and origins of animal Cys-loop ion channels. Genome Biol 6:R4

    Article  PubMed  Google Scholar 

  • Towers PR, Edwards B, Richmond JE, Sattelle DB (2005) The Caenorhabditis elegans lev-8 gene encodes a novel type of nicotinic acetylcholine receptor alpha subunit. J Neurochem 93:1–9

    Article  CAS  PubMed  Google Scholar 

  • Treinin M, Chalfie M (1995) A mutated acetylcholine receptor subunit causes neuronal degeneration in C. elegans. Neuron 14:871–877

    Article  CAS  PubMed  Google Scholar 

  • Troemel ER, Chou JH, Dwyer ND, Colbert HA, Bargmann CI (1995) Divergent seven transmembrane receptors are candidate chemosensory receptors in C. elegans. Cell 83:207–218

    Article  CAS  PubMed  Google Scholar 

  • Tsunoyama K, Gojobori T (1998) Evolution of nicotinic acetylcholine receptor subunits. Mol Biol Evol 15:518–527

    CAS  PubMed  Google Scholar 

  • Valentine JW, Jablonski D, Erwin DH (1999) Fossils, molecules and embryos: new perspectives on the Cambrian explosion. Development 126:851–859

    Google Scholar 

  • Vassilatis DK, Arena JP, Plasterk RH, Wilkinson HA, Schaeffer JM, Cully DF, Van der Ploeg LH (1997a) Genetic and biochemical evidence for a novel avermectin-sensitive chloride channel in Caenorhabditis elegans. J Biol Chem 272:33167–33174

    Article  CAS  Google Scholar 

  • Vassilatis DK, Elliston KO, Paress PS, Hamelin M, Arena JP, Schaeffer JM, Van der Ploeg LH, Cully DF (1997b) Evolutionary relationship of the ligand-gated ion channels and the avermectin-sensitive, glutamate-gated chloride channels. J Mol Evol 44:50150–50158

    Article  Google Scholar 

  • Wray GA, Levinton JS, Shapiro LH (1996) Molecular evidence for deep precambrian divergences among metazoan phyla. Science 274:568–573

    Article  CAS  Google Scholar 

  • Xue H (1998) Identification of major phylogenetic branches of inhibitory ligand-gated channel receptors. J Mol Evol 47:323–333

    Article  CAS  PubMed  Google Scholar 

  • Yassin L, Boaz G, Kahan T, Halevi S, Eshel M, Treinin M (2001) Characterization of the DEG-3/DES-2 receptor: a nicotinic acetylcholine receptor that mutates to cause neuronal degeneration. Mol Cell Neurosci 17:589–599

    Article  CAS  PubMed  Google Scholar 

  • Zheng Y, Hirschberg B, Yuan J, Wang AP, Hunt DC, Ludmerer SW, Schmatz DM, Cully DF (2002) Identification of two novel Drosophila melanogaster histamine-gated chloride channel subunits expressed in the eye. J Biol Chem 277:2000–2005

    Article  CAS  PubMed  Google Scholar 

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I would like to thank E. Abouheif and D. Schoen for critical reading of the manuscript.

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Correspondence to Joseph A. Dent.

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Dent, J.A. Evidence for a Diverse Cys-Loop Ligand-Gated Ion Channel Superfamily in Early Bilateria. J Mol Evol 62, 523–535 (2006). https://doi.org/10.1007/s00239-005-0018-2

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