Abstract
An extensive phylogenetic analysis of the nicotinic-acetylcholine-receptor subunit gene family has been performed by cladistic and phenetic methods. The conserved parts of amino acid sequences have been analyzed by CLUSTAL V and PHYLIP software. The structure of the genes was also taken in consideration. The results show that a first gene duplication may have occurred before the appearance of Bilateria. Three subfamilies then appeared: I-the neuronal α-bungarotoxin binding-site subunits (α7, α8); III-the neuronal nicotinic subunits (α2–α6, β2–β4), which also contain the muscle acetylcholine-binding subunit (α1); and IV—the muscle non-α subunits (β1, γ δ, ε). The Insecta subunits (subfamily II) could be orthologous to family III and IV. Several tissular switches of expression from neuron to muscle and the converse can be inferred from the extant expression of subunits and the reconstructed trees. The diversification of the neuronal nicotinic subfamily begins in the stem lineage of chordates, the last duplications occurring shortly before the onset of the mammalian lineage. Such evolution parallels the increase in complexity of the cholinergic systems.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Abbreviations
- α-Bgt:
-
α-bungarotoxin
- ACh:
-
acetylcholine
- MP:
-
maximum of parsimony
- MYA:
-
million years ago
- NJ:
-
neighbor-joining
- nAChR:
-
nicotinic acetylcholine receptor
References
Anand R, Conroy WG, Schoepfer R, Whiting P, Lindstrom J (1991) Neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes have a pentameric quaternary structure. J Biol Chem 266: 11192–11198
Anand R, Peng X, Lindstrom J (1993) Homomeric and native alpha7 acetylcholine receptors exhibit remarkably similar but non-identical pharmacological properties, suggesting that the native receptor is a heteromeric protein complex. FEBS Lett 327:241–246
Benton MJ (1990) Phylogeny of the major tetrapod groups: morphological data and divergence dates. J Mol Evol 30:409–424
Bertrand D, Galzi JL, Devillers-Thiéry A, Bertrand D, Changeux JP (1993) Stratification of the channel domain in neurotransmitter receptors. Curr Opin Cell Biol 5:688–693
Boulter J, O'Shea-Greenfield A, Duvoisin R, Connolly JG, Wada E, Jensen A, Gardner PD, Ballivet M, Deneris ES, McKinnon D, Heinemann Patrick J (1990) α3, α5, and β4: three members of the rat neuronal nicotinic acetylcholine receptor-related gene family form a gene cluster. J Biol Chem 265:4472–4482
Breer H, Kleene R, Hinz G (1985) Molecular forms and subunit structure of the acetylcholine receptor in the central nervous system of insects. J Neurosci 5:3386–3392
Brehm P, Okamura Y, Mandel G (1991) Ion channel evolution. Semin Neurosci 3:355–367
Britto LRG, Keyser KT, Lindstrom JM, Karten HJ (1992) Immunohistochemical localization of nicotinic acetylcholine receptor subunits in the mesencephalon and diencephalon of the chick (Gallus gallus). J Comp Neurol 317:325–340
Changeux JP, Kasai M, Lee CY (1970) The use of snake venom toxin to characterize the cholinergic receptor protein. Proc Natl Acad Sci USA 67:1241–1247
Changeux JP (1990) Functional architecture and dynamics of the nicotinic acetylcholine receptor: an allosteric ligand-gated ion channel. Fidia Res Found Neurosci Award Lectures 4:21–168
Clarke PBS, Schwartz RD, Paul SM, Pert CB, Pert A (1985) Nicotinic binding in rat brain: autoradiographic comparison of [3H]acetylcholine, [3H]nicotine and [125I]α-bungarotoxin. J Neurosci 5:1307–1315
Cockcroft VB, Osguthorpe DJ, Barnard EA, Friday AE, Lunt GG (1992) Ligand-gated channels. Homology and diversity. Mol Neurobiol 4:129–169
Conroy G, Vernallis AB, Berg DK (1992) The α5 gene product assembles with multiple acetylcholine receptor subunits to form distinctive receptor subtypes in brain. Neuron 9:679–691
Cooper E, Couturier S, Ballivet M (1991) Pentameric structure and subunit stoichiometry of a neuronal acetylcholine receptor. Nature 350:235–238
Couturier S, Bertrand D, Matter JM, Hernandez MC, Bertrand S, Millar N, Valera S, Barkas T, Ballivet M (1990) A neuronal nicotinic acetylcholine receptor subunit (a7) is developmentally regulated and forms a homo-oligomeric channel blocked by a-BTX. Neuron 5:847–856
Darlison MG, Hutton ML, Harvey RJ (1993) Molluscan ligand-gated ion-channel receptors. In: Pichon Y (ed) EXS 63, comparative molecular neurobiology. Birkhäuser, Basel, pp 48–64
Daubas P, Devillers-Thiéry A, Geoffroy B, Martinez S, Bessis A, Changeux JP (1990) Differential expression of the neuronal acetylcholine receptor α2 subunit gene during chick brain development. Neuron 5:49–60
Daubas P, Salmon AM, Zoli M, Geoffroy B, Devillers-Thiéry A, Bessis A, Médevielle F, Changeux JP (1993) Chicken neuronal acetylcholine receptor α2-subunit gene exhibits neuron-specific expression in the brain and spinal cord of transgenic mice. Proc Natl Acad Sci USA 90:2237–2241
Dayhoff MO (1979) Atlas of protein sequence and structure, vol 5, supplement 3, 1978. National Biomedical Research Foundation, Washington DC
Deneris ES, Boulter J, Swanson LW, Patrick J, Heinemann S (1989) β3: a new member of nicotinic acetylcholine receptor gene family is expressed in brain. J Biol Chem 264:6268–6272
Devillers-Thiéry A, Galzi JL, Eiselé JL, Bertrand S, Bertrand D, Changeux JP (1993) Functional architecture of the nicotinic acetylcholine receptor: a prototype of ligand-gated ion channels. J Memb Biol 136:97–112
Eck RV, Dayhoff MO (1966) Atlas of protein sequence and structure. National Biomedical Research Foundation, Silver Spring, MD
Ekström P (1987) Distribution of choline acetyltransferase-immunoreactive neurons in the brain of a cyprinid teleost (Phoxinus phoxinus L). J Comp Neurol 256:494–515
Estabrook GF, Johnson CS Jr, McMorris FR (1976) A mathematical foundation for the analysis of character compatibility. Math Biosci 23:181–187
Felsenstein J (1985) Confidence limits on phylogenies: an approach using the bootstrap. Evolution 39:783–791
Felsenstein J (1993) PHYLIP (phylogeny inference package) version 3.5c. Distributed by the author. Department of Genetics, University of Washington, Seattle
Feng DF, Doolittle RF (1987) Progressive sequence alignment as a prerequisite to correct phylogenetic trees. J Mol Evol 25:351–360
Fitch WW (1971) Toward defining the course of evolution: minimum change for a specified tree topology. Syst Zool 20:406–416
Flemming IT, Tornoe C, Riina HA, Coadwell J, Lewis JA, Sattelle DB (1993) Acetylcholine receptor molecules of the nematode Caenorhabditis elegans. In: Pichon Y (ed) EXS 63, comparative molecular neurobiology. Birkhäuser, Basel, pp 65–80
Galzi JL, Devillers-Thiéry 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
Galzi JL, Changeux JP (1994) Ligand-gated ion channel as unconventional allosteric proteins. Curr Opin Struct Biol 4:554–565
Gerschenfeld HM (1973) Chemical transmission in invertebrate central nervous systems and neuromuscular junctions. Physiol Rev 53:1–119
Greenberg ME, Ziff EB, Greene LA (1986) Stimulation of neuronal acetylcholine receptors induces rapid gene transcription. Science 234:80–83
Gundelfinger ED (1992) How complex is the nicotinic receptor system of insects? TINS 15:206–211
Hanke W, Breer H (1986) Channel properties of an insect neuronal acetylcholine receptor protein reconstituted in planar lipid bilayers. Nature 321:171–174
Higgins DG, Sharp PM (1988) CLUSTAL: a package for performing multiple sequence alignments on a microcomputer. Gene 73:237–244
Hill JA, Zoli M, Bourgeois JP, Changeux JP (1993) Immunocytochemical localization of a neuronal nicotinic receptor: The β2 subunit. J Neurosci 13:1551–1568
Jonas P, Baumann A, Merz B, Gundelfinger ED (1990) Structure and developmental expression of the Dal gene encoding a novel nicotinic acetylcholine receptor protein of Drosophila melanogaster. FEBS Lett 269:264–268
Karlin A (1993) Structure of nicotinic acetylcholine receptors. Curr Opin Neurobiol 3:299–309
Labandeira CC, Sepkoski JJ Jr (1993) Insect diversity in the fossil record. Science 261:310–315
Lake JA (1990) Origin of the metazoa. Proc Natl Acad Sci USA 87: 763–766
Lee CY, Chang CC (1966) Modes of actions of purified toxins from elapid venoms on neuro-muscular transmission. Mem Inst Butantan Sao Paulo 33:555–572
Leech CA, Sattelle DB (1993) Acetylcholine receptor/channel of insects. In: Pichon Y (ed) EXS 63, Comparative molecular neurobiology. Birkhäuser, Basel, pp 81–97
Le Quesne WJ (1969) A method of selection of characters in numerical taxonomy. Syst Zool 18:201–205
Luetje CW, Patrick J (1991) Both α- and β-subunits contribute to the agonist sensitivity of the neuronal nicotinic acetylcholine receptor. J Neurosci 11:837–845
Marshall J, Buckingham SD, Shingai R, Lunt GG, Goosey MW, Darlison MG, Satelle DB, Barnard EA (1990) Sequence and functional expression of a single α subunit of an insect nicotinic receptor. EMBO J 9:4391–4398
Mulle C, Vidal C, Benoit P, Changeux JP (1991) Existence of different subtypes of nicotinic acetylcholine receptors in the rat habenuloi-nterpeduncular system. J Neurosci 11:2588–2597
Ono JK, Salvaterra PM (1981) Snake alpha-toxin effects on cholinergic and noncholinergic responses of Aplysia californica neurons. J Neurosci 1:259–270
Revah F, Bertrand D, Galzi JL, Devillers-Thiéry A, Mulle C, Hussy N, Bertrand S, Ballivet M, Changeux JP (1991) Mutations in the channel domain alter desensitization of a neuronal nicotinic receptor. Nature 353:846–849
Role LW (1992) Diversity in primary structure and function of neuronal nicotinic acetylcholine receptor channels. Curr Opin Neurobiol 2:254–262
Saitou N, Nei M (1987) The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol Biol Evol 4:406–425
Sargent PB (1993) The diversity of neuronal nicotinic acetylcholine receptors. Anon Rev Neurosci 16:403–443
Sawruk E, Schloss P, Betz H, Schmitt B (1990) Heterogeneity of Drosophila nicotinic receptors: SAD, a novel developmentally regulated α-subunit. EMBO J 9:2671
Schloss P, Hermans-Borgmeyer I, Betz H, Gundelfinger ED (1988) Neuronal acetylcholine receptor in Drosophila: the ARD protein is a component of a high affinity α-bungarotoxin binding complex. EMBO J 7:2889–2894
Schoepfer R, Conroy WG, Whiting P, Gore M, Lindstrom J (1990) Brain α-bungarotoxin binding protein cDNAs and MAbs reveal subtypes of this branch of the ligand-gated ion channel gene superfamily. Neuron 5:35–48
Segerberg MA, Stretton AOW (1993) Actions of cholinergic drugs in the nematode Ascaris suum. Complex pharmacology of muscle and motorneurons. J Gen Physiol 101:271–296
Sneath PHA, Sokal RR (1973) Numerical taxonomy. Freeman, San Francisco
Vanfleteren JR, Van de Peer Y, Blaxter ML, Tweedie SAR, Trotman C, Lu L, Van Hauwaert ML, Moens L (1994) Molecular genealogy of some nematode taxa as based on cytochrome c and globin amino acid sequences. Mol Phylogen Evol 3:92–101
Vernallis AB, Conroy WG, Berg DK (1993) Neurons assemble acetylcholine receptors with as many as three kinds of subunits while maintaining subunit segregation among receptor subtypes. Neuron 10:451–464
Wada K, Ballivet M, Boulter J, Connolly J, Wada E, Deneris ES, Swanson LW, Heinemann S, Patrick J (1988) Functional expression of a new pharmacological subtype of brain nicotinic acetylcholine receptor. Science 240:330–334
Wada E, Wada K, Boulter J, Deneris E, Heinemann S, Patrick J, Swanson LW (1989) Distribution of α2, α3, α4 and β2 neuronal nicotinic receptor subunit mRNAs in the central nervous system: a hybridation histochemical study in the rat. J Comp Neurol 284: 314–335
Wada E, McKinnon D, Heinemann S, Patrick J, Swanson LW (1990) The distribution of mRNA encoded by a new member of the neuronal nicotinic acetylcholine receptor gene family (α5) in the rat central nervous system. Brain Res 526:45–53
Walker RJ, Colquhoun L, Holden-Dye L (1992) Pharmacological profiles of the GABA and acetylcholine receptors from the nematode, Ascaris suum. Acta Biol Hung 43:59–68
Whiting P, Schoepfer R, Lindstrom J, Priestley T (1991) Structural and pharmacological characterization of the major brain nicotinic acetylcholine receptor subtype stably expressed in mouse fibroblast. Mol Pharmacol 40:463–472
Wilbur WJ, Lipman DJ (1983) Rapid similarity searches of nucleic acid and protein data banks. Proc Natl Acad Sci USA 80:726–730
Zoli M, Le Novère N, Hill JA, Changeux JP (1995) Developmental regulation of nicotinic receptor subunit mRNAs in the rat central and peripheral nervous system. J Neurosci (in press)
Author information
Authors and Affiliations
Additional information
Correspondence to: N. Le Novère
Rights and permissions
About this article
Cite this article
Le Novere, N., Changeux, JP. Molecular evolution of the nicotinic acetylcholine receptor: An example of multigene family in excitable cells. J Mol Evol 40, 155–172 (1995). https://doi.org/10.1007/BF00167110
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00167110