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The Nicotinic Acetylcholine Receptor: A Member of the Superfamily of Ligand-Gated Ion Channels

  • Jean-Luc Galzi
  • Jean-Pierre Changeux
Conference paper
Part of the NATO ASI Series book series (volume 52)

Abstract

In the recent years, the methods of recombinant DNA technology have led to the identification of a large collection of amino acid sequences from several ligand gated ion channels, such as the nicotinic acetylcholine receptor from electric organ, muscle and brain, as well as glycine, GABA and glutamate receptors from brain. Structural and functional evidence support the view that these allosteric membrane proteins are pentameric hetero-oligomers, their distinctive pharmacological and physiological properties being associated with a defined subunit composition. Yet, still little is known about the actual three-dimension architecture of these oligomers and about the detailed structural mechanisms of the transitions which mediate fast and slow regulation of ion channel opening.

Keywords

Acetylcholine Receptor Nicotinic Acetylcholine Receptor Electric Organ Agonist Binding Site AChR Subunit 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. Abramson SN, Li Y, Culver P, Taylor P (1989) An analog of lophotoxin reacts covalently with Tyr 190 in the α-subunit of the nicotinic acetylcholine receptor. J. Biol. Chem. 264:12666–12672.PubMedGoogle Scholar
  2. Adams PR (1981) Acetylcholine receptor kinetics. J. Membrane Biol. 58:161–174.CrossRefGoogle Scholar
  3. Ascher P, Nowak L (1988) The role of divalent cations in the responses of central neurons to N-methyl-D-aspartate. J. Physiol. London, 399:247–266.PubMedGoogle Scholar
  4. Blount P, Merlie JP (1989) Molecular basis of the two nonequivalent ligand binding sites of the muscle nicotinic acetylcholine receptor. Neuron 3:349–357.PubMedCrossRefGoogle Scholar
  5. Brisson A, Unwin PNT (1985) Quaternary structure of the acetylcholine receptor. Nature 315:474–477.PubMedCrossRefGoogle Scholar
  6. Changeux JP (1981) The acetylcholine receptor: An “allosteric” membrane protein. “Harvey Lectures”. Acad. Press Inc. 75:85–254.Google Scholar
  7. Changeux JP, Devillers-Thiéry A, Chemouilli P (1984) Acetylcholine receptor: an allosteric protein. Science 225:1335–1345.PubMedCrossRefGoogle Scholar
  8. Changeux JP (1990) Functional architecture and dynamics of the nicotinic acetylcholine receptor: an allosteric ligand-gated ion channel. Fidia Research Foundation Neuroscience Award Lectures, volume 4. JP Changeux, RR Llinas, D Purves, FE Bloom eds, Raven Press Ltd, pp. 21–168.Google Scholar
  9. Charnet P, Labarca C, Leonard RJ, Vogelaar NJ, Czyzyk L, Gouin A, Davidson N, Lester HA (1990) An open-channel blocker interacts with adjacent turns of α-helices in the nicotinic acetylcholine receptor. Neuron 2:87–95.CrossRefGoogle Scholar
  10. Chothia C, Lesk AM, Tramontano A, Levitt M, Smith-Gill SJ, Air G, Sheriff S, Padlan EA, Davies D, Tulip WR, Comman PM, Spinelli S, Alzari PM, Poljak RJ (1989) Conformations of immunoglobulin hypervariable regions. Nature 342:877–883.PubMedCrossRefGoogle Scholar
  11. Claudio T, Ballivet M, Patrick J, Heinemann S (1983) Nucleotide and deduced amino acid sequences of Torpedo californica acetylcholine receptor gamma-subunit. Proc. Natl. Acad. Sci. USA 80:1111–1115.PubMedCrossRefGoogle Scholar
  12. Cohen JB, Boyd ND (1979) “Catalysis in Chemistry and Biochemistry”, B. Pulmann and O. Ginsburg, Eds (D. Eidel, Publ.).Google Scholar
  13. Damle VN, Karlin A (1978) Affinity labeling of one of two α-neurotoxin binding sites in acetylcholine receptor from Torpedo californica. Biochemistry 17:2039–2045.PubMedCrossRefGoogle Scholar
  14. Dennis M, Giraudat J, Kotzyba-Hibert F, Goeldner M, Hirth C, Chang JY, Lazure C, Chrétien M, Changeux JP. (1988) Amino acids of the Torpedo marmorata acetylcholine receptor a subunit labeled by a photoaffinity ligand for the acetylcholine binding site. Biochemistry 27:2346–2357.PubMedCrossRefGoogle Scholar
  15. Devillers-Thiery A, Giraudat J, Bentaboulet M, Changeux JP (1983) Complete mRNA coding sequence of the acetylcholine binding alpha subunit of Torpedo marmorata acetylcholine receptor: A model for the transmembrane organization of the polypeptide chain. Proc. Natl. Acad. Sci. USA 80:2067–2071.PubMedCrossRefGoogle Scholar
  16. Dowding AJ, Hall ZW (1987) Monoclonal antibodies specific for each of the two toxin-binding sites of Torpedo acetylcholine receptor. Biochemistry 26:6372–6381.PubMedCrossRefGoogle Scholar
  17. Galzi JL, Revah F, Black D, Goeldner M, Hirth C, Changeux JP. (1990) Identification of a novel amino acid α Tyr 93 within the active site of the acetylcholine receptor by photoaffinity labeling: additional evidence for a three-loop model of the acetylcholine binding site. J. Biol. Chem. 265:10430–10437.PubMedGoogle Scholar
  18. Giraudat J, Dennis M, Heidmann T, Chang JY, Changeux JP (1986) Structure of the high affinity binding site for noncompetitive blockers of the acetylcholine receptor: Serine-262 of the delta subunit is labeled by 3H chlorpromazine. Proc. Natl. Acad. Sci. USA 83:2719–2723.PubMedCrossRefGoogle Scholar
  19. Giraudat J, Dennis M, Heidmann T, Haumont PT, Lederer F, Changeux JP (1987) Structure of the high-affinity binding site for noncompetitive blockers of the acetylcholine receptor: H chlorpromazine labels homologous residues in the beta and delta chains. Biochemistry 26: 2410–2418.PubMedCrossRefGoogle Scholar
  20. Giraudat J, Galzi JL, Revah F, Changeux JP, Haumont PY, Lederer F (1989) The noncompetitive blocker [H]chlorpromazine labels segment M2 but not segment Ml of the nicotinic acetylcholine receptor alpha-subunit. FEBS Lett. 253:190–198.PubMedCrossRefGoogle Scholar
  21. Gregor P, Mano I, Maoz I, McKeown M, Teichberg VI (1989) Molecular structure of the chick cerebellar kainate-binding subunit of a putative glutamate receptor. Nature 342:689–692.PubMedCrossRefGoogle Scholar
  22. Grenningloh G, Rienitz A, Schmitt B, Methfessel C, Zensen M, Beyreuther K, Gundelfinger ED, Betz H (1987) The strychnine binding subunit of the glycine receptors shows homology with nicotinic acetylcholine receptors. Nature 328:215–220.PubMedCrossRefGoogle Scholar
  23. Guy RH, Hucho F (1987) The ion channel of the nicotinic acetylcholine receptor. Trends Neurosci. 10:318–321.CrossRefGoogle Scholar
  24. Haring R, Kloog Y, Kalir A, Sokolovsky M (1983) Species differences determine azido phencyclidine labeling pattern in desensitized nicotinic acetylcholine receptors. Biochem. Biophys. Res. Comm. 113:723–729.PubMedCrossRefGoogle Scholar
  25. Heidmann T, Changeux JP (1986) Characterization of the transient agonist-triggered state of the acetylcholine receptor rapidly labeled by the noncompetitive blocker [3H] chlor promazine: additional evidence for the open channel conformation. Biochemistry 25:6109–6113.PubMedCrossRefGoogle Scholar
  26. Heidmann T, Oswald RE, Changeux JP (1983) Multiple sites of action for noncompetitive blockers on acetylcholine receptor rich membrane fragments from Torpedo marmorata. Biochemistry 22:3112–3127.PubMedCrossRefGoogle Scholar
  27. Herz JM, Johnson DA, Taylor P (1989. Distance between the agonist and noncompetitive inhibitor sites on the nicotinic acetylcholine receptor. J. Biol. Chem. 264:12439–12448.PubMedGoogle Scholar
  28. Hess GP, Pasquale EB, Walker JW, McNamee MG (1982) Comparison of acetylcholine receptor-controlled cation flux in membrane vesicles form Torpedo californica and Electrophorus electricus: chemical kinetic measurements in the millisecond region. Proc. Natl. Acad. Sci. USA 79: 963–967.PubMedCrossRefGoogle Scholar
  29. Hollmann M, O’Shea-Greenfield, Rogers SW, Heinemann S (1989) Cloning by functional expression of a member of the glutamate receptor family. Nature 342:643–648.PubMedCrossRefGoogle Scholar
  30. Hucho FL (1986) The nicotinic acetylcholine receptor and its ion channel. Eur. J. Biochem. 158:211–226.PubMedCrossRefGoogle Scholar
  31. Hucho FL, Oberthür W, Lottspeich F (1986) The ion channel of the nicotinic acetylcholine receptor is formed by the homologous helices MII of the receptor subunits. FEBS Lett. 205:137–142.PubMedCrossRefGoogle Scholar
  32. Imoto K, Busch C, Sakmann B, Mishina M, Konno T, Nakai J, Bujo H, Mori Y, Fukuda K, Numa S (1988) Rings of negatively charged amino acids determine the acetylcholine receptor channel conductance. Nature 335: 645–648.PubMedCrossRefGoogle Scholar
  33. Kaldany RRJ, Karlin A (1983) Reaction of quinacrine mustard with the acetylcholine receptor from Torpedo californica: Functional consequences and sites of labeling. J. Biol. Chem. 258:6232–6242.PubMedGoogle Scholar
  34. Kao PN, Dwork AJ, Kaldany RRJ, Silver ML, Wideman J, Stein S, Karlin A (1984) Identification of the alpha-subunit half-cystine specifically labeled by an affinity reagent for the acetylcholine receptor binding site. J. Biol. Chem. 259:11662–11665.PubMedGoogle Scholar
  35. Karlin A (1980) Molecular properties of nicotinic acetylcholine receptors. “Cell Surface reviews” (Poste G, Nicolson, GL, Cotman, CW, Eds) 6, New York, 191–260.Google Scholar
  36. Klarsfeld A, Devillers-Thiery A, Giraudat J, Changeux JP (1984) A single gene codes for the nicotinic acetylcholine receptor alpha-subunit in Torpedo marmorata: Structural and developmental implications. EMBO J. 3:35–41.PubMedGoogle Scholar
  37. Kuhse J, Schmieden V, Betz H (1991) A single amino acid exchange alters the pharmacology of neonatal rat glycine receptor subunit. Neuron (in press).Google Scholar
  38. Langenbuch-Cachat J, Bon C, Goeldner M, Hirth C, Changeux JP (1988) Photoaffinity labeling by aryldiazonium derivatives of Torpedo marmorata acetylcholine receptor. Biochemistry 27:2337–2345.PubMedCrossRefGoogle Scholar
  39. Leonard RJ, Labarca CG, Charnet P, Davidson N, Lester HA (1988) Evidence that the M2 membrane-spanning region lines the ion channel pore of the nicotinic receptor. Science 242:1578–1581.PubMedCrossRefGoogle Scholar
  40. Mishina M, Tobimatsu T, Imoto K, Tanaka K, Fujita Y, Fukuda K, Kurasaki M, Takahashi H, Morimoto Y, Hirose T, Inayama S, Takahashi T, Kuno M, Numa S (1985) Location of functional regions of acetylcholine receptor alpha-subunit by site-directed mutagenesis. Nature 313:364–369.PubMedCrossRefGoogle Scholar
  41. Mitra AK, McCarthy MP, Stroud RM (1989) Three-dimensional structure of the nicotinic acetylcholine receptor and location of the major associated 43-kD cytoskeletal protein, determined at 22 Å by low dose electron microscopy and X-ray diffraction to 12.5 Å. J. Cell Biol. 109:755–774.PubMedCrossRefGoogle Scholar
  42. Muhn P, Hucho F (1983) Covalent labeling of the acetylcholine receptor from Torpedo electric tissue with the channel blocker [3H] triphenylmethylphosphonium by ultraviolet irradiation. Biochemistry 22:421–425.PubMedCrossRefGoogle Scholar
  43. Neubig RR, Cohen JB (1979) Equilibrium binding of (3H) tubocurarine and [3H] acetylcholine by Torpedo postsynaptic membranes: stoichiometry and ligand interactions. Biochemistry 18:5464–5475.PubMedCrossRefGoogle Scholar
  44. Noda M, Takahashi H, Tanabe T, Toyosato M, Kikyotani S, Furutani Y., Hirose T, Takashima H, Inayama S, Miyata T, Numa S (1983) Structural homology of Torpedo californica acetylcholine receptor subunits. Nature 302:528–532.PubMedCrossRefGoogle Scholar
  45. Oberthür W, Muhn P, Baumann H, Lottspeich F, Wittmann-Liebold B, Hucho F (1986) The reaction site of a noncompetitive antagonist in the delta-subunit of the nicotinic acetylcholine receptor. EMBO J. 5: 1815–1819.PubMedGoogle Scholar
  46. Oswald RE, Changeux JP (1982) Crosslinking of alpha-bungarotoxin to the acetylcholine receptor from Torpedo marmorata by ultraviolet light irradiation. FEBS Lett. 139:225–229.PubMedCrossRefGoogle Scholar
  47. Oswald R, Sobel A, Waksman G, Roques B, Changeux JP (1980) Selective labeling by [3H-]trimethisoquin azide of polypeptide chains present in acetylcholine receptor rich membranes from Torpedo marmorata. FEBS Lett. 111:29–34.PubMedCrossRefGoogle Scholar
  48. Pedersen SE, Cohen JB (1990a) d-tubocurarine binding sites are located at α-γ and α-δ subunit interfaces of the nicotinic acetylcholine receptor. Proc. Natl. Acad. Sci. USA 87:2785–2789.PubMedCrossRefGoogle Scholar
  49. Pedersen SE, Cohen JB. (1990b) [3H]-mepraodifen mustard reacts with glu-262 of the nicotinic acetylcholine receptor (AChR) α-subunit. Biophy. J. 57:126a.Google Scholar
  50. Perutz MF (1989) Mechanisms of cooperativity and allosteric regulation in proteins. Quarterly Rev. Biophys. 22:139–236.CrossRefGoogle Scholar
  51. Pritchett DB, Sontheimer H, Gorman CM, Kettenmann H, Seeburg PH, Schofield PR (1988) Transient expression shows ligand gating and allosteric potentiation of GABA receptor subunits. Science 242:1306–1308.PubMedCrossRefGoogle Scholar
  52. Revah F, Galzi JL, Giraudat J, Haumont PY, Lederer F, Changeux, JP (1990) The noncompetitive blocker [3H]chlorpromazine labels three amino acids of the acetylcholine receptor γ subunit: implications for the α helical organization of the MII segment and the structure of the ion channel. Proc. Natl. Acad. Sci. USA 87:4675–4679.PubMedCrossRefGoogle Scholar
  53. Reynolds JA, Karlin A (1978) Molecular weight in detergent solution of acetylcholine receptor from Torpedo californica. Biochemistry 17: 2035–2038.PubMedCrossRefGoogle Scholar
  54. Sakman B, Patlak J, Neher E (1980) Single acetylcholine activated channels show burst-kinetics in presence of desensitizing concentrations of agonist. Nature 286:71–73.CrossRefGoogle Scholar
  55. Shivers BD, Killisch I, Sprengel R, Sontheimer H, Köhler M, Schofield PR, Seeburg PH (1989) Two novel GABAA receptor subunits exist in distinct neuronal subpopulations. Neuron 33:327–337.CrossRefGoogle Scholar
  56. Toyoshima C, Unwin N (1988) Ion channel of acetylcholine receptor reconstructed from images of postsynaptic membranes. Nature 336:247–250.PubMedCrossRefGoogle Scholar
  57. Unwin N (1989) The structure of ion channels in membranes of excitable cells. Neuron 3:665–676.PubMedCrossRefGoogle Scholar
  58. Wada K, Dechesne CJ, Shimasaki S, King RG, Kusano K, Buonanno A, Hampson DR, Banner C, Wenthold RJ, Nakatani Y (1989) Sequence and expression of a frog brain complementary DNA encoding a kainate-binding protein. Nature 342:684–689.PubMedCrossRefGoogle Scholar
  59. Walker JW, Takeyasu K, McNamee MG (1982) Activation and inactivation kinetics of Torpedo californica acetylcholine receptor in reconstitued membranes. Biochemistry 21:5384–5389.PubMedCrossRefGoogle Scholar
  60. Weber M, Changeux JP (1974) Binding of Naja nigricollis 3H-alpha-toxin to membrane fragments from Electrophorus and Torpedo electric organs. 2. Effect of the cholinergic agonists and antagonists on the binding of the tritiated α-neurotoxin. Mol. Pharmacol. 10:13–34.Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1991

Authors and Affiliations

  • Jean-Luc Galzi
    • 1
  • Jean-Pierre Changeux
    • 1
  1. 1.UA CNRS D1284 “Neurobiologie Moléculaire” Département des BiotechnologiesInstitut PasteurParis Cedex 15France

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