On the Main Immunogenic Region of the Acetylcholine Receptor. Structure and Role in Myasthenia Gravis

  • S. J. Tzartos
  • D. Sophianos
  • A. Kordossi
  • I. Papadouli
  • I. Hadjidakis
  • C. Sakarellos
  • M. T. Cung
  • M. Marraud
Conference paper
Part of the NATO ASI Series book series (volume 38)

Abstract

The nicotinic acetylcholine receptor (AChR) from mammalian muscle and fish electric organ consists of four homologous subunits with the stoichiometry a2βγδ. Each subunit transverses the membrane at least four times (Changeux and Revan, 1987; Numa et al., 1983). The AChR molecule is the major autoantigen in the human autoimmune disease, myasthenia gravis (MG) (Willcox and Vincent, 1988). Anti-AChR antibodies result in loss of AChRs and also directly block the function of the remaining AChR molecules, thereby causing a defect in neuromuscular transmission.

Keywords

DMSO Amide Half Life Alanine Acetylcholine 

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References

  1. Barkas T, Mauron A, Roth B, Alliod C, Tzartos SJ, Ballivet M (1987) Mapping the main immunogenic region and toxin binding site of the nicotinic acetylcholine receptor. Science 235: 77–80PubMedCrossRefGoogle Scholar
  2. Barkas T, Gabriel J-M, Mauron A, Hughes GJ, Roth B, Alliod C, Tzartos SJ, Ballivet M (1988) Fine localisation of the main immunogenic region of the nicotinic acetylcholine receptor to residues 61–76 of the a-subunit. J Biol Chem 263: 5916–5920PubMedGoogle Scholar
  3. Changeux JP, Revah F (1987) The acetylcholine receptor molecule: allosteric sites and the ion channel. TINS 10: 245–250Google Scholar
  4. Cung MT, Marraud M, Hadjidakis I, Bairaktari H Sakarellos C, Kokla A, Tzartos S (1989) 2D–1H NMR study of a synthetic peptide containing the main immunogenic region of the Torpedo acetylcholine receptor. Biopolymers 28, 465–478PubMedCrossRefGoogle Scholar
  5. Gullick WJ, Tzartos SJ, Lindstrom J (1981) Monoclonal antibodies as probes of acetylcholine receptor structure. I. Peptide mapping. Biochemistry 20: 2173–2180PubMedCrossRefGoogle Scholar
  6. Kordossi A, Tzartos SJ (1987) Conformation of cytoplasmic segments of acetylcholine receptor a and ß subunits probed by monoclonal antibodies. Sensitivity of the antibody competition approach. EMBO J 6: 1605–1610PubMedGoogle Scholar
  7. Kordossi AA, Tzartos SJ (1989) Monoclonal antibodies against the main immunogenic region of the acetylcholine receptor. Mapping on the intact molecule. J NeuroimmunolGoogle Scholar
  8. Kubalek E, Ralston S, Lindstrom J and Unwin N (1987) Location of subunits within the acetylcholine receptor by electron image analysis of tubular crystals from Torpedo marmorata. J Cell Biol 105: 9–18PubMedCrossRefGoogle Scholar
  9. Lindstrom J, Schoepfer R, Whiting P (1987) Molecular studies of the neuronal nicotinic AchR family. Molecular Neurobiology 1: 281–337PubMedCrossRefGoogle Scholar
  10. Luther M A, Schoepfer R, Whiting P, Casey B, Blatt, Montal M S, Montal M, Lindstrom J (1989) A muscle acetylcholine receptor is expressed in the human cerebellar meduloblastoma cell line TE671. J NeurosciGoogle Scholar
  11. McAllister R M, Isaacs H, Rongey R, Peer M, Ann W, Soukup S W, Gardner M B (1977) Establishment of a human meduloblastoma cell line. Int J Cancer 20: 206–212PubMedCrossRefGoogle Scholar
  12. Merlie JP, Smith MM (1986) Synthesis and assembly of acetylcholine receptor, a multisubunit membrane glycoprotein. J Membr Biol 91: 1–10PubMedCrossRefGoogle Scholar
  13. Numa S et al. (1983) Molecular structure of the acetylcholine receptor. Cold Spring Harb Symp Quant Biol 48: 57–69PubMedGoogle Scholar
  14. Papadouli I, Potamianos S, Hadjidakis I, Bairaktari H, Tsikaris V, Sakarellos C, Cung MT, Marraud M, Tzartos ST (1989) Antigenic role of single residues within the main immunogenic region of the nicotinic acetylcholine receptor. SubmittedGoogle Scholar
  15. Ratnam M, Le Nguyen D, Rivier J, Sargent P, Lindstrom J (1986a) Transmembrane topography of the nicotinic acetylcholine receptor: immunochemical tests contradict theoretical predictions based on hydrophobicity profile. Biochemistry 25: 2633–2643PubMedCrossRefGoogle Scholar
  16. Ratnam M, Sargent P, Sarin V, Fox JL, Le Nguyen D, Rivier J, Criado M, Lindstrom J (1986b) Location of antigenic determinants on primary sequences of the subunits of the nicotinic acetylcholine receptor by peptide mapping. Biochemistry 25: 2621–2632PubMedCrossRefGoogle Scholar
  17. Sophianos D, Tzartos SJ (1989) Fab fragments of monoclonal antibodies protect the human acetylcholine receptor against antigenic modulation caused by myasthenic sera. SubmittedGoogle Scholar
  18. Stratton MR et al. (1989) Characterization of the human cell line TE671. CarcinogenesisGoogle Scholar
  19. Tzartos SJ, Lindstrom JL (1980) MAbs to probe acetylcholine receptor structure: Localization of the main immunogenic region and detection of similarities between subunits. Proc Natl Acad Sci USA 77: 755–759PubMedCrossRefGoogle Scholar
  20. Tzartos SJ, Seybold M, Lindstrom J (1982) Specificities of antibodies to acetylcholine receptors in sera from myasthenia gravis patients measured by monoclonal antibodies. Proc Natl Acad Sci USA 79: 188–192PubMedCrossRefGoogle Scholar
  21. Tzartos SJ, Sophianos D, Efthimiadis A (1985) Role of the main immunogenic region of acetylcholine receptor in myasthenia gravis. An Fab monoclonal antibodies protects against antigenic modulation by human sera. J Immunol 134: 2343–2349PubMedGoogle Scholar
  22. Tzartos SJ, Sophianos D, Zimmermann K, Starzinski-Powitz A (1986) Antigenic modulation of human muscle acetylcholine receptor by myasthenic sera. Serum titer determines receptor internalization. J Immunol 136: 3231–3237PubMedGoogle Scholar
  23. Tzartos SJ, Hochschwender S, Vasquez P, Lindstrom J (1987) Passive transfer of experimental autoimmune myasthenia gravis by monoclonal antibodies to the main immunogenic region of the acetylcholine receptor. J Neuroimmunol 15: 185–194PubMedCrossRefGoogle Scholar
  24. Tzartos SJ, Kokla A, Walgrave S, Conti-Tronconi B (1988) Localization of the main immunogenic region of human muscle acetylcholine receptor to residues 67–76 of the a-subunit. Proc Natl Acad Sci USA 85: 2800–2903CrossRefGoogle Scholar
  25. Tzartos SJ, Loutrari H, Tang F, Kokla A, Walgrave S, Milius R P, Conti-Tronconi B (1989) The main immunogenic region of Torpedo electroplax and human muscle acetylcholine receptor. Localization and micro-heterogeneity reveiled by the use of synthetic peptides. J NeurochemGoogle Scholar
  26. Willcox N, Vincent A (1988) Myasthenia gravis as an example of organ-specific autoimmune disease. In “Blymphocytes in human disease” A.G. Bird and J. Calvert, eds. Blackwells, Oxford, pp 469–506.Google Scholar
  27. Zhang Y, Tzartos SJ, Wekerle H (1988) B-T lymphocyte interactions in experimental autoimmune myasthenia gravis: antigen presentation by rat/mouse hybridoma lines secreting mAbs against the nicotinic acetylcholine receptor. Eur J Immunol 18: 211–218PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1990

Authors and Affiliations

  • S. J. Tzartos
    • 1
  • D. Sophianos
    • 1
  • A. Kordossi
    • 1
  • I. Papadouli
    • 1
  • I. Hadjidakis
    • 2
  • C. Sakarellos
    • 2
  • M. T. Cung
    • 3
  • M. Marraud
    • 3
  1. 1.Hellenic Pasteur InstituteAthensGreece
  2. 2.University of IoanninaIoanninaGreece
  3. 3.CNRS-UA-494, ENSIC-INPLNancyFrance

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