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Experientia

, Volume 52, Issue 12, pp 1083–1090 | Cite as

Allosteric proteins after thirty years: The binding and state functions of the neuronalα7 nicotinic acetylcholine receptors

  • S. J. Edelstein
  • J. -P. Changeux
Milti-Author Reviews

Abstract

A key statement of the 1965 Monod-Wyman-Changeux (MWC) model for allosteric proteins concerns the distinction between the ligand-binding function (\(\bar Y\)) and the relevant state function (\(\bar R\)). Sequential models predict overlapping behavior of the two functions. In contrast, a straightforward experimental consequence of the MWC model is that for an oligomeric protein the parameters which characterize the two functions should differ significantly. Two situations, where\(\bar R > \bar Y\) and the system ishyper-responsive or where\(\bar R< \bar Y\) and the system ishypo-responsive, have been encountered. Indeed, the hyper-responsive pattern was first observed for the enzyme aspartate transcarbamoylase, by comparing\(\bar Y\) with\(\bar R\) monitored by a change in sedimentation. Extensions of the theory to ligand-gated channels led to the suggestion that, on the one hand, hyper-responsive properties also occur with high-affinity mutants. On the other hand, native channels of the acetylcholine neuronalα7 receptor and low-affinity mutants of the glycine receptor can be interpreted in terms of the hypo-responsive pattern. For the ligand-gated channels, whereas\(\bar R\) is detected directly by ion flux, ligand binding has rarely been measured and the formation of desensitized states may complicate the analysis. However, stochastic models incorporating both binding and channel opening for single molecules predict differences that should be measurable with new experimental approaches, particularly fluorescence correlation spectroscopy.

Key words

Allosteric proteins MWC model ligand-gated channels neuronal nicotinic acetylcholine receptors stochastic models 

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References

  1. 1.
    Changeux J.-P. (1961) The feedback control mechanism of biosynthetic L-threonine deaminase by L-isoleucine. Cold Spring Harbor Symp. Quant. Biol.26: 313–318PubMedGoogle Scholar
  2. 2.
    Monod J. and Jacob F. (1961) General conclusions: telenomic mechanisms in cellular metabolism, growth, and differentiation. Cold Spring Harbor Symp. Quant. Biol.26: 389–401Google Scholar
  3. 3.
    Monod J., Changeux J.-P. and Jacob F. (1963) Allosteric proteins and cellular control systems. J. Molec. Biol.6: 306–329PubMedGoogle Scholar
  4. 4.
    Changeux J.-P. (1996) Neurotransmitter receptors in the changing brain: allosteric transitions, gene expression and pathology at the molecular level. In: The Nobel Symposium 1994: Individual Development over the Lifespan: Biological and Psychosocial Perspectives, pp. 107–138, Magnusson D. (ed.), Cambridge University Press, CambridgeGoogle Scholar
  5. 5.
    Monod J., Wyman J. and Changeux J.-P. (1965) On the nature of allosteric transitions: a plausible model. J. Molec. Biol.12: 88–118PubMedGoogle Scholar
  6. 6.
    Perutz M. F. (1989) Mechanisms of cooperativity and allosteric regulation in proteins. Quart. Rev. Biophys.22: 139–236Google Scholar
  7. 7.
    Rubin M. M. and Changeux J.-P. (1966) On the nature of allosteric transitions: implications of non-exclusive ligand binding. J. Molec. Biol.21: 265–274CrossRefPubMedGoogle Scholar
  8. 8.
    Changeux J.-P. and Rubin M. M. (1968) Allosteric interactions in aspartate transcarbamylase. III. Interpretations of experimental data in terms of the model of Monod, Wyman, and Changeux. Biochemistry7: 553–561PubMedGoogle Scholar
  9. 9.
    Pauling L. (1935) The oxygen equilibrium of hemoglobin and its structural interpretation. Proc. Natl. Acad. Sci. USA21: 186–191Google Scholar
  10. 10.
    Koshland D. E., Némethy G. and Filmer D. (1966) Comparison of experimental binding data and theoretical models in proteins containing subunits. Biochemistry5: 365–385PubMedGoogle Scholar
  11. 11.
    Schachman H. K. (1988) Can a simple model account for the allosteric transition of aspartate transcarbamoylase? J. Biol. Chem.263: 18583–18586PubMedGoogle Scholar
  12. 12.
    Kantrowitz E. R. and Lipscomb W. N. (1988)Escherichia coli aspartate transcarbamylase: the relation between structure and function. Science241: 669–674PubMedGoogle Scholar
  13. 13.
    Fetler L., Tauc P., Herve G., Moody M. F. and Vachette P. (1995) X-ray scattering titration of the quaternary structure transition of aspartate transcarbamylase with a bisubstrate analog: influence of nucleotide effectors. J. Molec. Biol.251: 243–255CrossRefPubMedGoogle Scholar
  14. 14.
    Weber K. (1968) New structural model ofE. coli aspartate transcarbamylase and the amino-acid sequence of the regulatory polypeptide chain. Nature218: 1116–1119PubMedGoogle Scholar
  15. 15.
    Wiley D. C. and Lipscomb W. N. (1968) Crystallographic determination of symmetry of aspartate transcarbamylase. Nature218: 1119–1121PubMedGoogle Scholar
  16. 16.
    Edelstein S. J., Schaad O., Henry E., Bertrand D. and Changeux J.-P. (1996) A kinetic mechanism for nicotinic acetylcholine receptors based on multiple allosteric transitions. Biol. Cybern. (in press)Google Scholar
  17. 17.
    Edelstein S. J. (1971) Extensions of the allosteric model for hemoglobin. Nature230: 224–227PubMedGoogle Scholar
  18. 18.
    Edelstein S. J. (1975) Cooperative interactions of hemoglobin. A. Rev. Biochem.44: 209–232CrossRefGoogle Scholar
  19. 19.
    Shulman R. G., Hopfield J. J. and Ogawa S. (1975) Allosteric interpretation of hemoglobin properties. Quart. Rev. Biophys.8: 325–420Google Scholar
  20. 20.
    Sawicki C. A. and Gibson Q. H. (1976) Quaternary conformational changes in human hemoglobin studied by laser photolysis of carboxyhemoglobin. J. Biol. Chem.251: 1533–1542PubMedGoogle Scholar
  21. 21.
    Rivetti C., Mozzarelli A., Rossi G. L., Henry E. R. and Eaton W. A. (1993) Oxygen binding by single crystals of hemoglobin. Biochemistry32: 2888–2906CrossRefPubMedGoogle Scholar
  22. 22.
    Edelstein S. J. (1996) An allosteric theory for hemoglobin incorporating asymmetric states to test the putative molecular model for cooperativity. J. Molec. Biol.257: 737–744CrossRefPubMedGoogle Scholar
  23. 23.
    Changeux J.-P., Thiéry J.-P., Tung T. and Kittel C. (1967) On the cooperativity of biological membranes. Proc. Natl. Acad. Sci. USA57: 335–341Google Scholar
  24. 24.
    Karlin A. (1967) On the application of ‘a plausible model’ of allosteric proteins to the receptor of acetylcholine. J. Theor. Biol.16: 306–320CrossRefPubMedGoogle Scholar
  25. 25.
    Edelstein S. J. (1972) An allosteric mechanism for the acetylcholine receptor. Biochem. Biophys. Res. Commun.48: 1160–1165CrossRefPubMedGoogle Scholar
  26. 26.
    Changeux J.-P., Devillers-Thiéry A. and Chemouilli P. (1984) Acetylcholine receptor: an allosteric protein. Science225: 1335–1345PubMedGoogle Scholar
  27. 27.
    Galzi J.-L., Edelstein S. J. and Changeux J.-P. (1996) The multiple phenotypes of allosteric receptor mutants. Proc. Natl. Acad. Sci. USA93: 1853–1858CrossRefPubMedGoogle Scholar
  28. 28.
    Galzi J.-L. and Changeux J.-P. (1994) Neurotransmitter-gated ion channels as unconventional allosteric proteins.Curr. Opinion in Structural Biol. 4: 554–565CrossRefGoogle Scholar
  29. 29.
    Katz B. and Thesleff S. (1957) A study of ‘desensitization’ produced by acetylcholine at the motor end-plate. J. Physiol.138: 83–80Google Scholar
  30. 30.
    Heidmann T. and Changeux J.-P. (1979) Fast kinetic studies on the interaction of a fluorescent agonist with the membranebound acetylcholine receptor fromTorpedo marmorata. Eur. J. Biochem.94: 255–279PubMedGoogle Scholar
  31. 31.
    Boyd N. D. and Cohen J. B. (1980) Kinetics of binding of [3H]acetylcholine and [3H]carbamoylcholine toTorpedo postsynaptic membranes: slow conformational transitions of the cholinergic receptor.Biochemistry 19: 5344–5353CrossRefPubMedGoogle Scholar
  32. 32.
    Trussell L. O. and Fischbach G. D. (1989) Glutamate receptor desensitization and its role in synaptic transmission. Neuron3: 209–218CrossRefPubMedGoogle Scholar
  33. 33.
    Colquhoun D., Jonas P. and Sakmann B. (1992) Action of brief pulses of glutamate on AMPA/Kainate receptors in patches from different neurones of rat hippocampal slices. J. Physiol.458: 261–287PubMedGoogle Scholar
  34. 34.
    Devillers-Thiéry A., Galzi J.-L., Eiselé J.-L., Bertrand S., Bertrand D. and Changeux J.-P. (1993) Functional architecture of the nicotinic acetylcholine receptor: a prototype of ligand-gated ion channels. J. Membrane Biol.136: 97–112Google Scholar
  35. 35.
    Karlin A. and Akabas M. H. (1995) Toward a structural basis for the function of nicotinic acetylcholine receptors. Neuron15: 1231–1244CrossRefPubMedGoogle Scholar
  36. 36.
    Bertrand D. and Changeux J.-P. (1995) Nicotinic receptor: an allosteric protein specialized for intracellular communication. Seminars in the Neurosciences7: 75–90CrossRefGoogle Scholar
  37. 37.
    McGehee D. S. and Role L. W. (1995) Physiological diversity of nicotinic acetylcholine receptors expressed by vertebrate neurons. A. Rev. Physiol.57: 521–546CrossRefGoogle Scholar
  38. 38.
    Palma E., Bertrand S., Binzoni T. and Bertrand D. (1996) Neural nicotinicα7 receptor expressed inXenopus oocytes presents five putative binding sites for methyllycaconitine. J. Physiol.491.1: 151–161Google Scholar
  39. 39.
    Heidmann T., Bernhardt J., Neumann E. and Changeux J.-P. (1983) Rapid kinetics of agonist binding and permeability response analyzed in parallel on acetylcholine receptor rich membranes fromTorpedo marmorata. Biochemistry22: 5452–5459CrossRefPubMedGoogle Scholar
  40. 40.
    Sakmann B., Patlak J. and Neher E. (1980) Single acetylcholine-activated channels show burst-kinetics in presence of desensitizing concentrations of agonist. Nature286: 71–73PubMedGoogle Scholar
  41. 41.
    Colquhoun D. and Sakmann B. (1985) Fast events in singlechannel currents activated by acetylcholine and its analogues at the frog muscle end-plate. J. Physiol.369: 501–557PubMedGoogle Scholar
  42. 42.
    Jackson M. B. (1988) Dependence of acetylcholine receptor channel kinetics on agonist concentration in cultured mouse muscle fibers. J. Physiol.397: 555–583PubMedGoogle Scholar
  43. 43.
    Sine S. M., Claudio T. and Sigworth F. J. (1990) Activation ofTorpedo acetylcholine receptors expressed in mouse fibroblasts; single channel current kinetics reveal distinct agonist binding affinities. J. Gen. Physiol.96: 395–437CrossRefPubMedGoogle Scholar
  44. 44.
    Eigen M. and Rigler R. (1994) Sorting single molecules: application to diagnostics and evolutionary biotechnology. Proc. Natl. Acad. Sci. USA91: 5740–5747PubMedGoogle Scholar
  45. 45.
    Rauer B., Neumann E., Widengren J. and Rigler R. (1996) Fluorscence correlation spectrometry of the interaction kinetics of tetramethylrhodaminα-bungarotoxin withTorpedo californica acetylcholine receptor. Biophys. Chem.58: 3–12CrossRefGoogle Scholar
  46. 46.
    Heidmann T. and Changeux J.-P. (1980) Interaction of a fluorescent agonist with the membrane-bound acetylcholine receptor fromTorpedo marmorata in the millisecond time range: resolution of an ‘intermediate’ conformational transition and evidence for positive cooperative effects. Biochem. Biophys. Res. Commun.97: 889–896PubMedGoogle Scholar
  47. 47.
    Revah F., Bertrand D., Galzi J.-L., Devillers-Thiéry A., Mulle C., Hussy N., Bertrand S., Ballivet M. and Changeux J.-P. (1991) Mutations in the channel domain alter desensitization of a neuronal nicotinic receptor. Nature353: 846–849CrossRefPubMedGoogle Scholar
  48. 48.
    Labarca C., Nowak M. W., Zhang H., Tang L., Desphande P. and Lester H. A. (1995) Channel gating governed symmetrically by conserved leucine residues in the M2 domain of nicotinic receptors. Nature376: 514–516CrossRefPubMedGoogle Scholar
  49. 49.
    Filatov G. N. and White M. M. (1995) The role of conserved leucines in the M2 domain of the acetylcholine receptor in channel gating. Molec. Pharmacol.48: 379–384Google Scholar
  50. 50.
    Bertrand D., Devillers-Thiéry A., Revah F., Galzi J.-L., Hussy N., Mulle C., Bertrand S., Ballivet M. and Changeux J.-P. (1992) Unconventional pharmacology of a neural nicotinic receptor mutated in the channel domain. Proc. Natl. Acad. Sci. USA89: 1261–1265PubMedGoogle Scholar
  51. 51.
    Bertrand S., Palma E., Corringer P. J., Edelstein S. J., Changeux J.-P. and Bertrand D. (1996) Methyllcaconitine a competitive inhibitor of theα7 desensitized open mutant L247T. Soc. Neurosci. Abstr.22: 1522Google Scholar
  52. 52.
    Devillers-Thiéry A., Galzi J.-L., Bertrand S., Changeux J.-P. and Bertrand D. (1992) Stratified organization of the nicotinic acetylcholine receptor channel. Neuroreport3: 1001–1004PubMedGoogle Scholar
  53. 53.
    Galzi J.-L., Devillers-Thiéry A., Hussy N., Bertrand S., Changeux J.-P. and Bertrand D. (1992) Mutations in the channel domain of a neuronal nicotinic receptor convert ion selectivity from cationic to anionic. Nature359: 500–505CrossRefPubMedGoogle Scholar
  54. 54.
    Ohno K., Hutchison D. O., Milone M., Brengham J. M., Bouzat C., Sine S. M. and Engel A. G. (1995) Congenital myasthenic syndrome caused by prolonged acetylcholine receptor channel openings due to a mutation in the M2 domain of the epsilon subunit. Proc. Natl. Acad. Sci. USA92: 758–762PubMedGoogle Scholar
  55. 55.
    Langosh D., Laube B., Rundström N., Schmieden V., Bormann J. and Betz H. (1994) Decreased agonist affinity and chloride conductance of mutant glycine receptors associated with human hereditary hyperekplexia. EMBO J.13: 4223–4228PubMedGoogle Scholar
  56. 56.
    Rajendra S., Lynch J., Pierce K. D., French C. R., Barry P. H. and Schofield P. R. (1995) Mutation of an arginine residue transforms beta-alanine and taurine from agonists into competitive antagonists. Neuron14: 169–175CrossRefPubMedGoogle Scholar
  57. 57.
    Castro N. G. and Albuquerque X. (1993) Brief-lifetime, fastinactivating ion channels account for theα-bungarotoxin-sensitive nicotinic response in hippocampal neurons. Neurosci. Lett.164: 137–140CrossRefPubMedGoogle Scholar
  58. 58.
    Lefkowitz R., Cotecchia S., Samama P. and Costa T. (1993) Constitutive activity of receptors coupled to guanine nucleotide regulatory proteins. Trends Pharmacol. Sci.14: 303–307CrossRefPubMedGoogle Scholar
  59. 59.
    Picones A. and Korenbrot J. I. (1995) Spontaneous, ligand-independent activity of the cGMP-gated ion channel in cone photoreceptors of fish. J. Physiol.485: 699–714PubMedGoogle Scholar
  60. 60.
    Tibbs G. R., Goulding E. H. and Siegelbaum S. A. (1995) Spontaneous opening of cyclic nucleotide-gated channels supports an allosteric model of activation. Biophys. J.68: A253Google Scholar
  61. 61.
    Yakel J. L., Lagrutta A., Adelman J. P. and North R. A. (1993) Single amino acid substitution affects desensitization of the 5-hydroxytryptamine type 3 receptor expressed inXenopus oocytes. Proc. Natl. Acad. Sci. USA90: 5030–5033PubMedGoogle Scholar
  62. 62.
    Hachiya N., Mihara K., Suda K., Horst M., Schatz G. and Lithgow T. (1995) Reconstitution of the initial steps of mitochondrial protein import. Nature376: 705–709CrossRefPubMedGoogle Scholar
  63. 63.
    Horst M., Hilfiker-Rothenfluh S., Oppliger W. and Schatz G. (1995) Dynamic interaction of the protein translocation systems in the inner and outer membranes of yeast mitochondria. EMBO J.14: 2293–2297PubMedGoogle Scholar
  64. 64.
    Schatz G. and Dobberstein B. (1996) Common principles of protein translocation across membranes. Science271: 1519–1526PubMedGoogle Scholar
  65. 65.
    Bardsley W. G. and Waight R. D. (1978) Factorability of the Hessian of the binding polynomial. The central issue concerning statistical ratios between binding constants, Hill plot slope and positive and negative cooperativity. J. Theor. Biol.72: 321–372CrossRefPubMedGoogle Scholar
  66. 66.
    Bardsley W. G., Woolfson R. and Mazat J.-P. (1980) Relationships between the magnitude of the Hill plot slopes, apparent binding constants and factorability of binding polynomials and their Hessians. J. Theor. Biol.85: 247–284CrossRefPubMedGoogle Scholar
  67. 67.
    Wyman J. and Gill S. J. (1990) Binding and Linkage: Functional Chemistry of Biological Macromolecules, Mill Valley, University Science BooksGoogle Scholar

Copyright information

© Birkhäuser Verlag 1996

Authors and Affiliations

  1. 1.Département de BiochimieUniversité de GenèveGenève 4(Switzerland)
  2. 2.Neurobiologie MoléculaireInstitut PasteurParis(France)

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