Acetylcholine Receptor Structure

  • Jie Luo
  • Jon M. Lindstrom
Part of the Current Clinical Neurology book series (CCNEU)


Over the past decade, studies of the atomic structure and the structural mechanism of nicotinic acetylcholine receptor (AChR) gating have reached an advanced stage. AChRs are members and prototypes of the superfamily of Cys-loop pentameric ligand-gated ion channels. AChRs are expressed by neurons throughout the central and peripheral nervous systems and also by many nonneuronal cell types all over the body. Although many different AChR subtypes formed by various combinations of 17 AChR subunits exhibit distinct distribution patterns, various functional properties, and diverse pharmacological characteristics, all subunits are highly homologous and share the same topographical features as subunits of other Cys-loop receptors. Here, focusing on the antigenic structure and functional structure of muscle AChRs, we describe how the antigenic structure of muscle AChRs accounts for the pathological mechanisms by which neuromuscular transmission is impaired in myasthenia gravis. This is contrasted with the antigenic structure of a neuronal AChR involved in autoimmune dysautonomia. We also summarize AChR mutations identified in muscle AChR subunits in myasthenic syndromes. This is contrasted with disease-causing mutations revealed in neuronal AChR subunits.


Nicotinic acetylcholine receptor Myasthenia gravis Myasthenic syndromes Autoimmune response Ion channel Gating Mutation 



The Lindstrom laboratory is supported by grants from the NIH.


  1. 1.
    Sine SM, Engel AG. Recent advances in Cys-loop receptor structure and function. Nature. 2006;440:448–55.PubMedCrossRefGoogle Scholar
  2. 2.
    Berg DK, Shoop RD, Chang KT. Nicotinic acetylcholine receptors in ganglionic transmission. In: Clementi F, Gotti C, Fornasari D, editors. Neuronal nicotinic receptors. New York: Springer; 2000. p. 247–67.CrossRefGoogle Scholar
  3. 3.
    Lindstrom J. The structures of neuronal nicotinic receptors. In: Clementi F, Gotti C, Fornasari D, editors. Neuronal nicotinic receptors. New York: Springer; 2000. p. 101–62.CrossRefGoogle Scholar
  4. 4.
    Kaiser S, Soliakov L, Wonnacott S. Presynaptic neuronal nicotinic receptors: pharmacology, heterogeneity, and cellular mechanisms. In: Clementi F, Gotti C, Fornasari D, editors. Neuronal nicotinic receptors. New York: Springer; 2000. p. 193–211.CrossRefGoogle Scholar
  5. 5.
    Zoli M. Distribution of cholinergic neurons in the mammalian brain with special reference to their relationship with neuronal nicotinic receptors. In: Clementi F, Gotti C, Fornasari D, editors. Neuronal nicotinic receptors. New York: Springer; 2000. p. 13–30.CrossRefGoogle Scholar
  6. 6.
    Grando SA. Cholinergic control of epidermal cohesion. Exp Dermatol. 2006;15:265–82.PubMedCrossRefGoogle Scholar
  7. 7.
    Sekhon HS, Jia Y, Raab R, Kuryatov A, Pankow JF, Whitsett JA, Lindstrom J, Spindel ER. Prenatal nicotine increases pulmonary α7 nicotinic receptor expression and alters fetal lung development in monkeys. J Clin Invest. 1999;103:637–47.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Macklin KD, Maus AD, Pereira EF, Albuquerque EX, Conti-Fine BM. Human vascular endothelial cells express functional nicotinic acetylcholine receptors. J Pharmacol Exp Ther. 1998;287:435–9.PubMedGoogle Scholar
  9. 9.
    Maus AD, Pereira EF, Karachunski PI, Horton RM, Navaneetham D, Macklin K, Cortes WS, et al. Human and rodent bronchial epithelial cells express functional nicotinic acetylcholine receptors. Mol Pharmacol. 1998;54:779–88.PubMedCrossRefGoogle Scholar
  10. 10.
    Hamano R, Takahashi HK, Iwagaki H, Yoshino T, Nishibori M, Tanaka N. Stimulation of α7 nicotinic acetylcholine receptor inhibits CD14 and the toll-like receptor 4 expression in human monocytes. Shock. 2006;26:358–64.PubMedCrossRefGoogle Scholar
  11. 11.
    Rosas-Ballina M, Goldstein RS, Gallowitsch-Puerta M, Yang L, Valdes-Ferrer SI, Patel NB, et al. The selective α7 agonist GTS-21 attenuates cytokine production in human whole blood and human monocytes activated by ligands for TLR2, TLR3, TLR4, TLR9, and RAGE. Mol Med. 2009;15:195–202.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Yoshikawa H, Kurokawa M, Ozaki N, Nara K, Atou K, Takada E, Kamochi H, Suzuki N. Nicotine inhibits the production of proinflammatory mediators in human monocytes by suppression of I-κB phosphorylation and nuclear factor-κB transcriptional activity through nicotinic acetylcholine receptor α7. Clin Exp Immunol. 2006;146:116–23.Google Scholar
  13. 13.
    Sato K, Nagayama H, Tadokoro K, Juji T, Takahashi TA. Extracellular signal-regulated kinase, stress-activated protein kinase/c-Jun N-terminal kinase, and p38mapk are involved in IL-10-mediated selective repression of TNF-α-induced activation and maturation of human peripheral blood monocyte-derived dendritic cells. J Immunol. 1999;162:3865–72.PubMedGoogle Scholar
  14. 14.
    Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature. 2000;405:458–62.PubMedCrossRefGoogle Scholar
  15. 15.
    de Lucas-Cerrillo AM, Maldifassi MC, Arnalich F, Renart J, Atienza G, Serantes R, et al. Function of partially duplicated human α7 nicotinic receptor subunit CHRFAM7A gene: potential implications for the cholinergic anti-inflammatory response. J Biol Chem. 2011;286:594–606.Google Scholar
  16. 16.
    Wang H, Liao H, Ochani M, Justiniani M, Lin X, Yang L, et al. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med. 2004;10:1216–21.PubMedCrossRefGoogle Scholar
  17. 17.
    Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, et al. Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature. 2003;421:384–8.PubMedCrossRefGoogle Scholar
  18. 18.
    De Rosa MJ, Dionisio L, Agriello E, Bouzat C, Esandi Mdel C. α7 nicotinic acetylcholine receptor modulates lymphocyte activation. Life Sci. 2009;85:444–9.PubMedCrossRefGoogle Scholar
  19. 19.
    Razani-Boroujerdi S, Boyd RT, Davila-Garcia MI, Nandi JS, Mishra NC, Singh SP, et al. T cells express α7-nicotinic acetylcholine receptor subunits that require a functional TCR and leukocyte-specific protein tyrosine kinase for nicotine-induced Ca2+ response. J Immunol. 2007;179:2889–98.PubMedCrossRefGoogle Scholar
  20. 20.
    Kawashima K, Yoshikawa K, Fujii YX, Moriwaki Y, Misawa H. Expression and function of genes encoding cholinergic components in murine immune cells. Life Sci. 2007;80:2314–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Skok MV, Kalashnik EN, Koval LN, Tsetlin VI, Utkin YN, Changeux JP, et al. Functional nicotinic acetylcholine receptors are expressed in B lymphocyte-derived cell lines. Mol Pharmacol. 2003;64:885–9.PubMedCrossRefGoogle Scholar
  22. 22.
    Engel AG, Ohno K, Sine SM. Sleuthing molecular targets for neurological diseases at the neuromuscular junction. Nat Rev Neurosci. 2003;4:339–52.PubMedCrossRefGoogle Scholar
  23. 23.
    Combi R, Dalpra L, Tenchini ML, Ferini-Strambi L. Autosomal dominant nocturnal frontal lobe epilepsy--a critical overview. J Neurol. 2004;251:923–34.PubMedCrossRefGoogle Scholar
  24. 24.
    Steinlein OK. Neuronal nicotinic receptors in human epilepsy. Eur J Pharmacol. 2000;393:243–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Becchetti A, Aracri P, Meneghini S, Brusco S, Amadeo A. The role of nicotinic acetylcholine receptors in autosomal dominant nocturnal frontal lobe epilepsy. Front Physiol. 2015;6:22.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Ferini-Strambi L, Sansoni V, Combi R. Nocturnal frontal lobe epilepsy and the acetylcholine receptor. Neurologist. 2012;18:343–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Lindstrom JM. Acetylcholine receptors and myasthenia. Muscle Nerve. 2000;23:453–77.PubMedCrossRefGoogle Scholar
  28. 28.
    Vernino S, Ermilov LG, Sha L, Szurszewski JH, Low PA, Lennon VA. Passive transfer of autoimmune autonomic neuropathy to mice. J Neurosci. 2004;24:7037–42.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Vernino S, Low PA, Fealey RD, Stewart JD, Farrugia G, Lennon VA. Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N Engl J Med. 2000;343:847–55.PubMedCrossRefGoogle Scholar
  30. 30.
    Vernino S, Hopkins S, Wang Z. Autonomic ganglia, acetylcholine receptor antibodies, and autoimmune ganglionopathy. Auton Neurosci. 2009;146:3–7.PubMedCrossRefGoogle Scholar
  31. 31.
    Grando SA. Autoimmunity to keratinocyte acetylcholine receptors in pemphigus. Dermatology. 2000;201:290–5.PubMedCrossRefGoogle Scholar
  32. 32.
    Tapper AR, McKinney SL, Nashmi R, Schwarz J, Deshpande P, Labarca C, Whiteaker P, et al. Nicotine activation of α4* receptors: sufficient for reward, tolerance, and sensitization. Science. 2004;306:1029–32.PubMedCrossRefGoogle Scholar
  33. 33.
    Peto R, Lopez AD, Boreham J, Thun M, Heath C Jr. Mortality from tobacco in developed countries: indirect estimation from national vital statistics. Lancet. 1992;339:1268–78.PubMedCrossRefGoogle Scholar
  34. 34.
    Heeschen C, Jang JJ, Weis M, Pathak A, Kaji S, Hu RS, et al. Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis. Nat Med. 2001;7:833–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Hurst RS, Hajos M, Raggenbass M, Wall TM, Higdon NR, Lawson JA, et al. A novel positive allosteric modulator of the α7 neuronal nicotinic acetylcholine receptor: in vitro and in vivo characterization. J Neurosci. 2005;25:4396–405.PubMedCrossRefGoogle Scholar
  36. 36.
    Lloyd GK, Williams M. Neuronal nicotinic acetylcholine receptors as novel drug targets. J Pharmacol Exp Ther. 2000;292:461–7.PubMedGoogle Scholar
  37. 37.
    Quik M, McIntosh JM. Striatal α6* nicotinic acetylcholine receptors: potential targets for Parkinson’s disease therapy. J Pharmacol Exp Ther. 2006;316:481–9.PubMedCrossRefGoogle Scholar
  38. 38.
    Jurado-Coronel JC, Avila-Rodriguez M, Capani F, Gonzalez J, Moran VE, Barreto GE. Targeting the nicotinic acetylcholine receptors (nAChRs) in astrocytes as a potential therapeutic target in Parkinson’s disease. Curr Pharm Des. 2016;22:1305–11.PubMedCrossRefGoogle Scholar
  39. 39.
    Haydar SN, Dunlop J. Neuronal nicotinic acetylcholine receptors – targets for the development of drugs to treat cognitive impairment associated with schizophrenia and Alzheimer’s disease. Curr Top Med Chem. 2010;10:144–52.PubMedCrossRefGoogle Scholar
  40. 40.
    Quik M, Bordia T, Zhang D, Perez XA. Nicotine and nicotinic receptor drugs: potential for Parkinson’s disease and drug-induced movement disorders. Int Rev Neurobiol. 2015;124:247–71.PubMedCrossRefGoogle Scholar
  41. 41.
    Coe JW, Brooks PR, Wirtz MC, Bashore CG, Bianco KE, Vetelino MG, et al. 3,5-Bicyclic aryl piperidines: a novel class of α4β2 neuronal nicotinic receptor partial agonists for smoking cessation. Bioorg Med Chem Lett. 2005;15:4889–97.PubMedCrossRefGoogle Scholar
  42. 42.
    Cahill K, Lindson-Hawley N, Thomas KH, Fanshawe TR, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev. 2016;(5):CD006103.Google Scholar
  43. 43.
    Karlin A, Akabas MH. Toward a structural basis for the function of nicotinic acetylcholine receptors and their cousins. Neuron. 1995;15:1231–44.PubMedCrossRefGoogle Scholar
  44. 44.
    Galzi JL, Devillers-Thiery A, Hussy N, Bertrand S, Changeux JP, Bertrand D. Mutations in the channel domain of a neuronal nicotinic receptor convert ion selectivity from cationic to anionic. Nature. 1992;359:500–5.PubMedCrossRefGoogle Scholar
  45. 45.
    Eisele JL, Bertrand S, Galzi JL, Devillers-Thiery A, Changeux JP, Bertrand D. Chimaeric nicotinic-serotonergic receptor combines distinct ligand binding and channel specificities. Nature. 1993;366:479–83.PubMedCrossRefGoogle Scholar
  46. 46.
    Jackson MB. Perfection of a synaptic receptor: kinetics and energetics of the acetylcholine receptor. Proc Natl Acad Sci U S A. 1989;86:2199–203.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Kummer TT, Misgeld T, Sanes JR. Assembly of the postsynaptic membrane at the neuromuscular junction: paradigm lost. Curr Opin Neurobiol. 2006;16:74–82.PubMedCrossRefGoogle Scholar
  48. 48.
    Lindstrom J. Purification and cloning of nicotinic acetylcholine receptors. In: Arneric SP, Brioni D, editors. Neuronal nicotinic receptors: pharmacology and therapeutic opportunities. New York: Wiley; 1999. p. 3–23.Google Scholar
  49. 49.
    Changeux J-P, Edelstein SJ. Nicotinic acetylcholine receptors: from molecular biology to cognition. New York: Odile Jacob; 2005.Google Scholar
  50. 50.
    Unwin N. Refined structure of the nicotinic acetylcholine receptor at 4Å resolution. J Mol Biol. 2005;346:967–89.Google Scholar
  51. 51.
    Patrick J, Lindstrom J. Autoimmune response to acetylcholine receptor. Science. 1973;180:871–2.PubMedCrossRefGoogle Scholar
  52. 52.
    Tzartos SJ, Barkas T, Cung MT, Mamalaki A, Marraud M, Orlewski P, Papanastasiou D, et al. Anatomy of the antigenic structure of a large membrane autoantigen, the muscle-type nicotinic acetylcholine receptor. Immunol Rev. 1998;163:89–120.PubMedCrossRefGoogle Scholar
  53. 53.
    Tzartos SJ, Lindstrom JM. Monoclonal antibodies used to probe acetylcholine receptor structure: localization of the main immunogenic region and detection of similarities between subunits. Proc Natl Acad Sci U S A. 1980;77:755–9.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Maimone MM, Merlie JP. Interaction of the 43 kd postsynaptic protein with all subunits of the muscle nicotinic acetylcholine receptor. Neuron. 1993;11:53–66.PubMedCrossRefGoogle Scholar
  55. 55.
    Unwin N. The Croonian Lecture 2000. Nicotinic acetylcholine receptor and the structural basis of fast synaptic transmission. Philos Trans R Soc Lond B Biol Sci. 2000;355:1813–29.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Unwin N, Fujiyoshi Y. Gating movement of acetylcholine receptor caught by plunge-freezing. J Mol Biol. 2012;422:617–34.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Du J, Lu W, Wu S, Cheng Y, Gouaux E. Glycine receptor mechanism elucidated by electron cryo-microscopy. Nature. 2015;526:224–9.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Morales-Perez CL, Noviello CM, Hibbs RE. X-ray structure of the human α4β2 nicotinic receptor. Nature. 2016;538:411–5.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Brejc K, van Dijk WJ, Klaassen RV, Schuurmans M, van Der Oost J, Smit AB, et al. Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature. 2001;411:269–76.PubMedCrossRefGoogle Scholar
  60. 60.
    Celie PH, van Rossum-Fikkert SE, van Dijk WJ, Brejc K, Smit AB, Sixma TK. Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures. Neuron. 2004;41:907–14.PubMedCrossRefGoogle Scholar
  61. 61.
    Hansen SB, Sulzenbacher G, Huxford T, Marchot P, Taylor P, Bourne Y. Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations. EMBO J. 2005;24:3635–46.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Smit AB, Syed NI, Schaap D, van Minnen J, Klumperman J, Kits KS, et al. A glia-derived acetylcholine-binding protein that modulates synaptic transmission. Nature. 2001;411:261–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Beroukhim R, Unwin N. Three-dimensional location of the main immunogenic region of the acetylcholine receptor. Neuron. 1995;15:323–31.PubMedCrossRefGoogle Scholar
  64. 64.
    Lee WY, Sine SM. Principal pathway coupling agonist binding to channel gating in nicotinic receptors. Nature. 2005;438:243–7.PubMedCrossRefGoogle Scholar
  65. 65.
    Bouzat C, Gumilar F, Spitzmaul G, Wang HL, Rayes D, Hansen SB, et al. Coupling of agonist binding to channel gating in an ACh-binding protein linked to an ion channel. Nature. 2004;430:896–900.PubMedCrossRefGoogle Scholar
  66. 66.
    Grutter T, Changeux JP. Nicotinic receptors in wonderland. Trends Biochem Sci. 2001;26:459–63.PubMedCrossRefGoogle Scholar
  67. 67.
    Wells GB, Anand R, Wang F, Lindstrom J. Water-soluble nicotinic acetylcholine receptor formed by α7 subunit extracellular domains. J Biol Chem. 1998;273:964–73.PubMedCrossRefGoogle Scholar
  68. 68.
    Huang S, Li SX, Bren N, Cheng K, Gomoto R, Chen L, Sine SM. Complex between α-bungarotoxin and an α7 nicotinic receptor ligand-binding domain chimaera. Biochem J. 2013;454:303–10.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Li SX, Huang S, Bren N, Noridomi K, Dellisanti CD, Sine SM, et al. Ligand-binding domain of an α7-nicotinic receptor chimera and its complex with agonist. Nat Neurosci. 2011;14:1253–9.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Wilson G, Karlin A. Acetylcholine receptor channel structure in the resting, open, and desensitized states probed with the substituted-cysteine-accessibility method. Proc Natl Acad Sci U S A. 2001;98:1241–8.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Sussman JL, Harel M, Frolow F, Oefner C, Goldman A, Toker L, et al. Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein. Science. 1991;253:872–9.PubMedCrossRefGoogle Scholar
  72. 72.
    Fu DX, Sine SM. Asymmetric contribution of the conserved disulfide loop to subunit oligomerization and assembly of the nicotinic acetylcholine receptor. J Biol Chem. 1996;271:31479–84.PubMedCrossRefGoogle Scholar
  73. 73.
    Das MK, Lindstrom J. Epitope mapping of antibodies to acetylcholine receptor α subunits using peptides synthesized on polypropylene pegs. Biochemistry. 1991;30:2470–7.PubMedCrossRefGoogle Scholar
  74. 74.
    Conroy WG, Liu Z, Nai Q, Coggan JS, Berg DK. PDZ-containing proteins provide a functional postsynaptic scaffold for nicotinic receptors in neurons. Neuron. 2003;38:759–71.PubMedCrossRefGoogle Scholar
  75. 75.
    Jeanclos EM, Lin L, Treuil MW, Rao J, DeCoster MA, Anand R. The chaperone protein 14-3-3η interacts with the nicotinic acetylcholine receptor α4 subunit. Evidence for a dynamic role in subunit stabilization. J Biol Chem. 2001;276:28281–90.Google Scholar
  76. 76.
    Keller SH, Lindstrom J, Ellisman M, Taylor P. Adjacent basic amino acid residues recognized by the COP I complex and ubiquitination govern endoplasmic reticulum to cell surface trafficking of the nicotinic acetylcholine receptor α-Subunit. J Biol Chem. 2001;276:18384–91.PubMedCrossRefGoogle Scholar
  77. 77.
    Keller SH, Lindstrom J, Taylor P. Involvement of the chaperone protein calnexin and the acetylcholine receptor β-subunit in the assembly and cell surface expression of the receptor. J Biol Chem. 1996;271:22871–7.PubMedCrossRefGoogle Scholar
  78. 78.
    Keller SH, Taylor P. Determinants responsible for assembly of the nicotinic acetylcholine receptor. J Gen Physiol. 1999;113:171–6.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Wang JM, Zhang L, Yao Y, Viroonchatapan N, Rothe E, Wang ZZ. A transmembrane motif governs the surface trafficking of nicotinic acetylcholine receptors. Nat Neurosci. 2002;5:963–70.PubMedCrossRefGoogle Scholar
  80. 80.
    Fenster CP, Beckman ML, Parker JC, Sheffield EB, Whitworth TL, Quick MW, et al. Regulation of α4β2 nicotinic receptor desensitization by calcium and protein kinase C. Mol Pharmacol. 1999;55:432–43.PubMedGoogle Scholar
  81. 81.
    Miles K, Huganir RL. Regulation of nicotinic acetylcholine receptors by protein phosphorylation. Mol Neurobiol. 1988;2:91–124.PubMedCrossRefGoogle Scholar
  82. 82.
    Williams BM, Temburni MK, Levey MS, Bertrand S, Bertrand D, Jacob MH. The long internal loop of the α 3 subunit targets nAChRs to subdomains within individual synapses on neurons in vivo. Nat Neurosci. 1998;1:557–62.PubMedCrossRefGoogle Scholar
  83. 83.
    Bouzat C, Bren N, Sine SM. Structural basis of the different gating kinetics of fetal and adult acetylcholine receptors. Neuron. 1994;13:1395–402.PubMedCrossRefGoogle Scholar
  84. 84.
    Hales TG, Dunlop JI, Deeb TZ, Carland JE, Kelley SP, Lambert JJ, et al. Common determinants of single channel conductance within the large cytoplasmic loop of 5-hydroxytryptamine type 3 and α4β2 nicotinic acetylcholine receptors. J Biol Chem. 2006;281:8062–71.PubMedCrossRefGoogle Scholar
  85. 85.
    Curtis L, Buisson B, Bertrand S, Bertrand D. Potentiation of human α4β2 neuronal nicotinic acetylcholine receptor by estradiol. Mol Pharmacol. 2002;61:127–35.PubMedCrossRefGoogle Scholar
  86. 86.
    Paradiso K, Zhang J, Steinbach JH. The C terminus of the human nicotinic α4β2 receptor forms a binding site required for potentiation by an estrogenic steroid. J Neurosci. 2001;21:6561–8.PubMedGoogle Scholar
  87. 87.
    Le Novere N, Changeux JP. Molecular evolution of the nicotinic acetylcholine receptor: an example of multigene family in excitable cells. J Mol Evol. 1995;40:155–72.PubMedCrossRefGoogle Scholar
  88. 88.
    Duvoisin RM, Deneris ES, Patrick J, Heinemann S. The functional diversity of the neuronal nicotinic acetylcholine receptors is increased by a novel subunit: β 4. Neuron. 1989;3:487–96.PubMedCrossRefGoogle Scholar
  89. 89.
    Couturier S, Bertrand D, Matter JM, Hernandez MC, Bertrand S, Millar N, et al. A neuronal nicotinic acetylcholine receptor subunit (α 7) is developmentally regulated and forms a homo-oligomeric channel blocked by α-BTX. Neuron. 1990;5:847–56.PubMedCrossRefGoogle Scholar
  90. 90.
    Anand R, Conroy WG, Schoepfer R, Whiting P, Lindstrom J. Neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes have a pentameric quaternary structure. J Biol Chem. 1991;266:11192–8.PubMedGoogle Scholar
  91. 91.
    Cooper E, Couturier S, Ballivet M. Pentameric structure and subunit stoichiometry of a neuronal nicotinic acetylcholine receptor. Nature. 1991;350:235–8.PubMedCrossRefGoogle Scholar
  92. 92.
    Boorman JP, Groot-Kormelink PJ, Sivilotti LG. Stoichiometry of human recombinant neuronal nicotinic receptors containing the β3 subunit expressed in Xenopus oocytes. J Physiol. 2000;529(Pt 3):565–77.Google Scholar
  93. 93.
    Kuryatov A, Olale F, Cooper J, Choi C, Lindstrom J. Human α6 AChR subtypes: subunit composition, assembly, and pharmacological responses. Neuropharmacology. 2000;39:2570–90.PubMedCrossRefGoogle Scholar
  94. 94.
    Harpsoe K, Ahring PK, Christensen JK, Jensen ML, Peters D, Balle T. Unraveling the high- and low-sensitivity agonist responses of nicotinic acetylcholine receptors. J Neurosci. 2011;31:10759–66.PubMedCrossRefGoogle Scholar
  95. 95.
    Mazzaferro S, Benallegue N, Carbone A, Gasparri F, Vijayan R, Biggin PC, et al. Additional acetylcholine (ACh) binding site at α4/α4 interface of (α4β2)2α4 nicotinic receptor influences agonist sensitivity. J Biol Chem. 2011;286:31043–54.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Jain A, Kuryatov A, Wang J, Kamenecka TM, Lindstrom J. Unorthodox acetylcholine binding sites formed by α5 and β3 accessory subunits in α4β2* nicotinic acetylcholine receptors. J Biol Chem. 2016;291:23452–63.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Jin X, Bermudez I, Steinbach JH. The nicotinic α5 subunit can replace either an acetylcholine-binding or nonbinding subunit in the α4β2* neuronal nicotinic receptor. Mol Pharmacol. 2014;85:11–7.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Wang J, Kuryatov A, Sriram A, Jin Z, Kamenecka TM, Kenny PJ, et al. An accessory agonist binding site promotes activation of α4β2* nicotinic acetylcholine receptors. J Biol Chem. 2015;290:13907–18.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Kuryatov A, Luo J, Cooper J, Lindstrom J. Nicotine acts as a pharmacological chaperone to up-regulate human α4β2 acetylcholine receptors. Mol Pharmacol. 2005;68:1839–51.PubMedGoogle Scholar
  100. 100.
    Nelson ME, Kuryatov A, Choi CH, Zhou Y, Lindstrom J. Alternate stoichiometries of α4β2 nicotinic acetylcholine receptors. Mol Pharmacol. 2003;63:332–41.PubMedCrossRefGoogle Scholar
  101. 101.
    Zhou Y, Nelson ME, Kuryatov A, Choi C, Cooper J, Lindstrom J. Human α4β2 acetylcholine receptors formed from linked subunits. J Neurosci. 2003;23:9004–15.PubMedGoogle Scholar
  102. 102.
    Wu J, Liu Q, Tang P, Mikkelsen JD, Shen J, Whiteaker P, Yakel JL. Heteromeric α7β2 nicotinic acetylcholine receptors in the brain. Trends Pharmacol Sci. 2016;37:562–74.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Schoepfer R, Conroy WG, Whiting P, Gore M, Lindstrom J. Brain α-bungarotoxin binding protein cDNAs and MAbs reveal subtypes of this branch of the ligand-gated ion channel gene superfamily. Neuron. 1990;5:35–48.PubMedCrossRefGoogle Scholar
  104. 104.
    Elgoyhen AB, Vetter DE, Katz E, Rothlin CV, Heinemann SF, Boulter J. α10: a determinant of nicotinic cholinergic receptor function in mammalian vestibular and cochlear mechanosensory hair cells. Proc Natl Acad Sci U S A. 2001;98:3501–6.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Lustig LR, Peng H, Hiel H, Yamamoto T, Fuchs PA. Molecular cloning and mapping of the human nicotinic acetylcholine receptor α10 (CHRNA10). Genomics. 2001;73:272–83.PubMedCrossRefGoogle Scholar
  106. 106.
    Forsayeth JR, Kobrin E. Formation of oligomers containing the β3 and β4 subunits of the rat nicotinic receptor. J Neurosci. 1997;17:1531–8.PubMedGoogle Scholar
  107. 107.
    Fucile S, Barabino B, Palma E, Grassi F, Limatola C, Mileo AM, et al. α5 Subunit forms functional α3 β4 α5 nAChRs in transfected human cells. Neuroreport. 1997;8:2433–6.PubMedCrossRefGoogle Scholar
  108. 108.
    Groot-Kormelink PJ, Luyten WH, Colquhoun D, Sivilotti LG. A reporter mutation approach shows incorporation of the “orphan” subunit β3 into a functional nicotinic receptor. J Biol Chem. 1998;273:15317–20.PubMedCrossRefGoogle Scholar
  109. 109.
    Vailati S, Hanke W, Bejan A, Barabino B, Longhi R, Balestra B, et al. Functional α6-containing nicotinic receptors are present in chick retina. Mol Pharmacol. 1999;56:11–9.PubMedCrossRefGoogle Scholar
  110. 110.
    Wang F, Gerzanich V, Wells GB, Anand R, Peng X, Keyser K, et al. Assembly of human neuronal nicotinic receptor α5 subunits with α3, β2, and β4 subunits. J Biol Chem. 1996;271:17656–65.PubMedCrossRefGoogle Scholar
  111. 111.
    Conroy WG, Berg DK. Neurons can maintain multiple classes of nicotinic acetylcholine receptors distinguished by different subunit compositions. J Biol Chem. 1995;270:4424–31.PubMedCrossRefGoogle Scholar
  112. 112.
    Gotti C, Moretti M, Zanardi A, Gaimarri A, Champtiaux N, Changeux JP, et al. Heterogeneity and selective targeting of neuronal nicotinic acetylcholine receptor (nAChR) subtypes expressed on retinal afferents of the superior colliculus and lateral geniculate nucleus: identification of a new native nAChR subtype α3β2(α5 or β3) enriched in retinocollicular afferents. Mol Pharmacol. 2005;68:1162–71.PubMedCrossRefGoogle Scholar
  113. 113.
    Lena C, de Kerchove D’Exaerde A, Cordero-Erausquin M, Le Novere N, del Mar Arroyo-Jimenez M, et al. Diversity and distribution of nicotinic acetylcholine receptors in the locus ceruleus neurons. Proc Natl Acad Sci U S A. 1999;96:12126–31.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Zoli M, Moretti M, Zanardi A, McIntosh JM, Clementi F, Gotti C. Identification of the nicotinic receptor subtypes expressed on dopaminergic terminals in the rat striatum. J Neurosci. 2002;22:8785–9.PubMedGoogle Scholar
  115. 115.
    Nelson ME, Wang F, Kuryatov A, Choi CH, Gerzanich V, Lindstrom J. Functional properties of human nicotinic AChRs expressed by IMR-32 neuroblastoma cells resemble those of α3β4 AChRs expressed in permanently transfected HEK cells. J Gen Physiol. 2001;118:563–82.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Shoop RD, Chang KT, Ellisman MH, Berg DK. Synaptically driven calcium transients via nicotinic receptors on somatic spines. J Neurosci. 2001;21:771–81.PubMedGoogle Scholar
  117. 117.
    Klink R, de Kerchove d’Exaerde A, Zoli M, Changeux JP. Molecular and physiological diversity of nicotinic acetylcholine receptors in the midbrain dopaminergic nuclei. J Neurosci. 2001;21:1452–63.PubMedGoogle Scholar
  118. 118.
    Ramirez-Latorre J, Yu CR, Qu X, Perin F, Karlin A, Role L. Functional contributions of α5 subunit to neuronal acetylcholine receptor channels. Nature. 1996;380:347–51.PubMedCrossRefGoogle Scholar
  119. 119.
    Gerzanich V, Wang F, Kuryatov A, Lindstrom J. α 5 Subunit alters desensitization, pharmacology, Ca++ permeability and Ca++ modulation of human neuronal α 3 nicotinic receptors. J Pharmacol Exp Ther. 1998;286:311–20.PubMedGoogle Scholar
  120. 120.
    Tsetlin VI, Hucho F. Snake and snail toxins acting on nicotinic acetylcholine receptors: fundamental aspects and medical applications. FEBS Lett. 2004;557:9–13.PubMedCrossRefGoogle Scholar
  121. 121.
    Ibanez-Tallon I, Miwa JM, Wang HL, Adams NC, Crabtree GW, Sine SM, et al. Novel modulation of neuronal nicotinic acetylcholine receptors by association with the endogenous prototoxin lynx1. Neuron. 2002;33:893–903.PubMedCrossRefGoogle Scholar
  122. 122.
    Chimienti F, Hogg RC, Plantard L, Lehmann C, Brakch N, Fischer J, et al. Identification of SLURP-1 as an epidermal neuromodulator explains the clinical phenotype of Mal de Meleda. Hum Mol Genet. 2003;12:3017–24.PubMedCrossRefGoogle Scholar
  123. 123.
    Arredondo J, Chernyavsky AI, Webber RJ, Grando SA. Biological effects of SLURP-1 on human keratinocytes. J Invest Dermatol. 2005;125:1236–41.PubMedCrossRefGoogle Scholar
  124. 124.
    Arredondo J, Chernyavsky AI, Jolkovsky DL, Webber RJ, Grando SA. SLURP-2: a novel cholinergic signaling peptide in human mucocutaneous epithelium. J Cell Physiol. 2006;208:238–45.PubMedCrossRefGoogle Scholar
  125. 125.
    Jones AK, Sattelle DB. Functional genomics of the nicotinic acetylcholine receptor gene family of the nematode, Caenorhabditis elegans. BioEssays. 2004;26:39–49.PubMedCrossRefGoogle Scholar
  126. 126.
    Jones AK, Elgar G, Sattelle DB. The nicotinic acetylcholine receptor gene family of the pufferfish, Fugu rubripes. Genomics. 2003;82:441–51.PubMedCrossRefGoogle Scholar
  127. 127.
    Bocquet N, Prado de Carvalho L, Cartaud J, Neyton J, Le Poupon C, Taly A, et al. A prokaryotic proton-gated ion channel from the nicotinic acetylcholine receptor family. Nature. 2007;445:116–9.PubMedCrossRefGoogle Scholar
  128. 128.
    Hilf RJ, Dutzler R. X-ray structure of a prokaryotic pentameric ligand-gated ion channel. Nature. 2008;452:375–9.PubMedCrossRefGoogle Scholar
  129. 129.
    Hilf RJ, Dutzler R. Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel. Nature. 2009;457:115–8.PubMedCrossRefGoogle Scholar
  130. 130.
    Basak S, Schmandt N, Gicheru Y, Chakrapani S. Crystal structure and dynamics of a lipid-induced potential desensitized-state of a pentameric ligand-gated channel. Elife. 2017;6:6.CrossRefGoogle Scholar
  131. 131.
    Pan J, Chen Q, Willenbring D, Mowrey D, Kong XP, Cohen A, et al. Structure of the pentameric ligand-gated ion channel GLIC bound with anesthetic ketamine. Structure. 2012;20:1463–9.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Bohler S, Gay S, Bertrand S, Corringer PJ, Edelstein SJ, Changeux JP, et al. Desensitization of neuronal nicotinic acetylcholine receptors conferred by N-terminal segments of the β 2 subunit. Biochemistry. 2001;40:2066–74.PubMedCrossRefGoogle Scholar
  133. 133.
    Prince RJ, Sine SM. Acetylcholine and epibatidine binding to muscle acetylcholine receptors distinguish between concerted and uncoupled models. J Biol Chem. 1999;274:19623–9.PubMedCrossRefGoogle Scholar
  134. 134.
    Kuffler SW, Yoshikami D. The number of transmitter molecules in a quantum: an estimate from iontophoretic application of acetylcholine at the neuromuscular synapse. J Physiol. 1975;251:465–82.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Steinbach JH, Chen Q. Antagonist and partial agonist actions of d-tubocurarine at mammalian muscle acetylcholine receptors. J Neurosci. 1995;15:230–40.PubMedGoogle Scholar
  136. 136.
    Malany S, Osaka H, Sine SM, Taylor P. Orientation of α-neurotoxin at the subunit interfaces of the nicotinic acetylcholine receptor. Biochemistry. 2000;39:15388–98.PubMedCrossRefGoogle Scholar
  137. 137.
    Magleby KL. Neuromuscular transmission. In: Engel AG, Franzini-Armstrong C, editors. Myology: basic and clinical, vol. 1994. 2nd ed. New York: McGraw-Hill; 1994. p. 442–63.Google Scholar
  138. 138.
    Gunderson CH, Lehmann CR, Sidell FR, Jabbari B. Nerve agents: a review. Neurology. 1992;42:946–50.PubMedCrossRefGoogle Scholar
  139. 139.
    Benowitz NL. Pharmacology of nicotine: addiction and therapeutics. Annu Rev Pharmacol Toxicol. 1996;36:597–613.PubMedCrossRefGoogle Scholar
  140. 140.
    Dani JA, Ji D, Zhou FM. Synaptic plasticity and nicotine addiction. Neuron. 2001;31:349–52.PubMedCrossRefGoogle Scholar
  141. 141.
    Picciotto MR, Caldarone BJ, King SL, Zachariou V. Nicotinic receptors in the brain. Links between molecular biology and behavior. Neuropsychopharmacology. 2000;22:451–65.PubMedCrossRefGoogle Scholar
  142. 142.
    Kopta C, Steinbach JH. Comparison of mammalian adult and fetal nicotinic acetylcholine receptors stably expressed in fibroblasts. J Neurosci. 1994;14:3922–33.PubMedGoogle Scholar
  143. 143.
    Papke RL, Meyer E, Nutter T, Uteshev VV. α7 receptor-selective agonists and modes of α7 receptor activation. Eur J Pharmacol. 2000;393:179–95.PubMedCrossRefGoogle Scholar
  144. 144.
    Corringer PJ, Le Novere N, Changeux JP. Nicotinic receptors at the amino acid level. Annu Rev Pharmacol Toxicol. 2000;40:431–58.PubMedCrossRefGoogle Scholar
  145. 145.
    Miyazawa A, Fujiyoshi Y, Unwin N. Structure and gating mechanism of the acetylcholine receptor pore. Nature. 2003;423:949–55.PubMedCrossRefGoogle Scholar
  146. 146.
    Froehner SC. Identification of exposed and buried determinants of the membrane-bound acetylcholine receptor from Torpedo californica. Biochemistry. 1981;20:4905–15.PubMedCrossRefGoogle Scholar
  147. 147.
    Tzartos SJ, Seybold ME, Lindstrom JM. Specificities of antibodies to acetylcholine receptors in sera from myasthenia gravis patients measured by monoclonal antibodies. Proc Natl Acad Sci U S A. 1982;79:188–92.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Luo J, Taylor P, Losen M, de Baets MH, Shelton GD, Lindstrom J. Main immunogenic region structure promotes binding of conformation-dependent myasthenia gravis autoantibodies, nicotinic acetylcholine receptor conformation maturation, and agonist sensitivity. J Neurosci. 2009;29:13898–908.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Lindstrom J, Luo J, Kuryatov A. Myasthenia gravis and the tops and bottoms of AChRs: antigenic structure of the MIR and specific immunosuppression of EAMG using AChR cytoplasmic domains. Ann N Y Acad Sci. 2008;1132:29–41.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Saedi MS, Anand R, Conroy WG, Lindstrom J. Determination of amino acids critical to the main immunogenic region of intact acetylcholine receptors by in vitro mutagenesis. FEBS Lett. 1990;267:55–9.PubMedCrossRefGoogle Scholar
  151. 151.
    Luo J, Lindstrom J. Antigenic structure of the human muscle nicotinic acetylcholine receptor main immunogenic region. J Mol Neurosci. 2010;40:217–20.PubMedCrossRefGoogle Scholar
  152. 152.
    Noridomi K, Watanabe G, Hansen MN, Han GW, Chen L. Structural insights into the molecular mechanisms of myasthenia gravis and their therapeutic implications. Elife. 2017;25:6.Google Scholar
  153. 153.
    Lindstrom J, Shelton D, Fujii Y. Myasthenia gravis. Adv Immunol. 1988;42:233–84.PubMedCrossRefGoogle Scholar
  154. 154.
    Lindstrom J. An assay for antibodies to human acetylcholine receptor in serum from patients with myasthenia gravis. Clin Immunol Immunopathol. 1977;7:36–43.PubMedCrossRefGoogle Scholar
  155. 155.
    Engel AG. Myasthenia gravis and myasthenic disorders. New York: Oxford University Press; 2012.CrossRefGoogle Scholar
  156. 156.
    Lindstrom J, Luo J. Myasthenogenicity of the main immunogenic region. Ann N Y Acad Sci. 2012;1274:9–13.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Luo J, Lindstrom J. Myasthenogenicity of the main immunogenic region and endogenous muscle nicotinic acetylcholine receptors. Autoimmunity. 2012;45:245–52.PubMedCrossRefGoogle Scholar
  158. 158.
    Drachman DB. The biology of myasthenia gravis. Ann Rev Neurosci. 1981;4:195–225.PubMedCrossRefGoogle Scholar
  159. 159.
    Drachman DB, Angus CW, Adams RN, Michelson JD, Hoffman GJ. Myasthenic antibodies cross-link acetylcholine receptors to accelerate degradation. N Engl J Med. 1978;298:1116–22.PubMedCrossRefGoogle Scholar
  160. 160.
    Heinemann S, Bevan S, Kullberg R, Lindstrom J, Rice J. Modulation of acetylcholine receptor by antibody against the receptor. Proc Natl Acad Sci U S A. 1977;74:3090–4.PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Blatt Y, Montal MS, Lindstrom JM, Montal M. Monoclonal antibodies specific to the β and γ subunits of the Torpedo acetylcholine receptor inhibit single-channel activity. J Neurosci. 1986;6:481–6.PubMedGoogle Scholar
  162. 162.
    Criado M, Mulet J, Castillo M, Gerber S, Sala S, Sala F. The loop between β-strands β 2 and β 3 and its interaction with the N-terminal α-helix is essential for biogenesis of α 7 nicotinic receptors. J Neurochem. 2010;112:103–11.PubMedCrossRefGoogle Scholar
  163. 163.
    Shelton GD, Cardinet GH, Lindstrom JM. Canine and human myasthenia gravis autoantibodies recognize similar regions on the acetylcholine receptor. Neurology. 1988;38:1417–23.PubMedCrossRefGoogle Scholar
  164. 164.
    Weinberg CB, Hall ZW. Antibodies from patients with myasthenia gravis recognize determinants unique to extrajunctional acetylcholine receptors. Proc Natl Acad Sci U S A. 1979;76:504–8.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Burges J, Wray DW, Pizzighella S, Hall Z, Vincent A. A myasthenia gravis plasma immunoglobulin reduces miniature endplate potentials at human endplates in vitro. Muscle Nerve. 1990;13:407–13.PubMedCrossRefGoogle Scholar
  166. 166.
    Vincent A, Newland C, Brueton L, Beeson D, Riemersma S, Huson SM, et al. Arthrogryposis multiplex congenita with maternal autoantibodies specific for a fetal antigen. Lancet. 1995;346:24–5.PubMedCrossRefGoogle Scholar
  167. 167.
    Beeson D, Bond AP, Corlett L, Curnow SJ, Hill ME, Jacobson LW, et al. Thymus, thymoma, and specific T cells in myasthenia gravis. Ann N Y Acad Sci. 1998;841:371–87.PubMedCrossRefGoogle Scholar
  168. 168.
    Conti-Fine BM, Navaneetham D, Karachunski PI, Raju R, Diethelm-Okita B, Okita D, et al. T cell recognition of the acetylcholine receptor in myasthenia gravis. Ann N Y Acad Sci. 1998;841:283–308.PubMedCrossRefGoogle Scholar
  169. 169.
    Fujii Y, Lindstrom J. Specificity of the T cell immune response to acetylcholine receptor in experimental autoimmune myasthenia gravis. Response to subunits and synthetic peptides. J Immunol. 1988;140:1830–7.PubMedGoogle Scholar
  170. 170.
    Hohlfeld R, Wekerle H. The immunopathogenesis of myasthenia gravis. In: Engel AG, editor. Myasthenia gravis and myasthenic disorders. New York: Oxford University Press; 1999. p. 87–104.Google Scholar
  171. 171.
    Raju R, Spack EG, David CS. Acetylcholine receptor peptide recognition in HLA DR3-transgenic mice: in vivo responses correlate with MHC-peptide binding. J Immunol. 2001;167:1118–24.PubMedCrossRefGoogle Scholar
  172. 172.
    Ong B, Willcox N, Wordsworth P, Beeson D, Vincent A, Altmann D, et al. Critical role for the Val/Gly86 HLA-DR β dimorphism in autoantigen presentation to human T cells. Proc Natl Acad Sci U S A. 1991;88:7343–7.PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Christadoss P, Lindstrom JM, Melvold RW, Talal N. Mutation at I-A β chain prevents experimental autoimmune myasthenia gravis. Immunogenetics. 1985;21:33–8.PubMedCrossRefGoogle Scholar
  174. 174.
    Christadoss P, Poussin M, Deng C. Animal models of myasthenia gravis. Clin Immunol. 2000;94:75–87.PubMedCrossRefGoogle Scholar
  175. 175.
    Hague DW, Humphries HD, Mitchell MA, Shelton GD. Risk factors and outcomes in cats with acquired myasthenia gravis (2001-2012). J Vet Intern Med. 2015;29:1307–12.PubMedPubMedCentralCrossRefGoogle Scholar
  176. 176.
    Shelton GD, Lindstrom JM. Spontaneous remission in canine myasthenia gravis: implications for assessing human MG therapies. Neurology. 2001;57:2139–41.PubMedCrossRefGoogle Scholar
  177. 177.
    Greco M, Cofano P, Lobreglio G. Seropositivity for West Nile virus antibodies in patients affected by myasthenia gravis. J Clin Med Res. 2016;8:196–201.PubMedPubMedCentralCrossRefGoogle Scholar
  178. 178.
    Leis AA, Szatmary G, Ross MA, Stokic DS. West Nile virus infection and myasthenia gravis. Muscle Nerve. 2014;49:26–9.Google Scholar
  179. 179.
    Molko N, Simon O, Guyon D, Biron A, Dupont-Rouzeyrol M, Gourinat AC. Zika virus infection and myasthenia gravis: report of 2 cases. Neurology. 2017;88:1097–8.PubMedCrossRefGoogle Scholar
  180. 180.
    Cavalcante P, Maggi L, Colleoni L, Caldara R, Motta T, Giardina C, Antozzi C, Berrih-Aknin S, Bernasconi P, Mantegazza R. Inflammation and Epstein-Barr virus infection are common features of myasthenia gravis thymus: possible roles in pathogenesis. Autoimmune Dis. 2011;2011:213092.Google Scholar
  181. 181.
    Cavalcante P, Serafini B, Rosicarelli B, Maggi L, Barberis M, Antozzi C, et al. Epstein-Barr virus persistence and reactivation in myasthenia gravis thymus. Ann Neurol. 2010;67:726–38.PubMedGoogle Scholar
  182. 182.
    Ascherio A, Munger KL. 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: Epstein-Barr virus and multiple sclerosis: epidemiological evidence. Clin Exp Immunol. 2010;160:120–4.PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    Fraser KB, Haire M, Millar JH, McCrea S. Increased tendency to spontaneous in-vitro lymphocyte transformation in clinically active multiple sclerosis. Lancet. 1979;2:175–6.PubMedGoogle Scholar
  184. 184.
    Sumaya CV, Myers LW, Ellison GW, Ench Y. Increased prevalence and titer of Epstein-Barr virus antibodies in patients with multiple sclerosis. Ann Neurol. 1985;17:371–7.PubMedCrossRefGoogle Scholar
  185. 185.
    Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med. 2003;349:1526–33.PubMedCrossRefGoogle Scholar
  186. 186.
    James JA, Kaufman KM, Farris AD, Taylor-Albert E, Lehman TJ, Harley JB. An increased prevalence of Epstein-Barr virus infection in young patients suggests a possible etiology for systemic lupus erythematosus. J Clin Invest. 1997;100:3019–26.PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    Zandman-Goddard G, Berkun Y, Barzilai O, Boaz M, Blank M, Ram M, et al. Exposure to Epstein-Barr virus infection is associated with mild systemic lupus erythematosus disease. Ann N Y Acad Sci. 2009;1173:658–63.PubMedCrossRefGoogle Scholar
  188. 188.
    Ferrell PB, Aitcheson CT, Pearson GR, Tan EM. Seroepidemiological study of relationships between Epstein-Barr virus and rheumatoid arthritis. J Clin Invest. 1981;67:681–7.PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    Klatt T, Ouyang Q, Flad T, Koetter I, Buhring HJ, Kalbacher H, et al. Expansion of peripheral CD8+ CD28- T cells in response to Epstein-Barr virus in patients with rheumatoid arthritis. J Rheumatol. 2005;32:239–51.PubMedGoogle Scholar
  190. 190.
    Fust G. The role of the Epstein-Barr virus in the pathogenesis of some autoimmune disorders – similarities and differences. Eur J Microbiol Immunol (Bp). 2011;1:267–78.CrossRefGoogle Scholar
  191. 191.
    Russell AS, Lindstrom JM. Penicillamine-induced myasthenia gravis associated with antibodies to acetylcholine receptor. Neurology. 1978;28:847–9.PubMedCrossRefGoogle Scholar
  192. 192.
    Vincent A, Newsom-Davis J, Martin V. Anti-acetylcholine receptor antibodies in D-penicillamine-associated myasthenia gravis. Lancet. 1978;1:1254.PubMedCrossRefGoogle Scholar
  193. 193.
    Penn AS, Low BW, Jaffe IA, Luo L, Jacques JJ. Drug-induced autoimmune myasthenia gravis. Ann N Y Acad Sci. 1998;841:433–49.PubMedCrossRefGoogle Scholar
  194. 194.
    Keesey J, Lindstrom J, Cokely H. Anti-acetylcholine receptor antibody in neonatal myasthenia gravis. N Engl J Med. 1977;296:55.PubMedGoogle Scholar
  195. 195.
    Vernet-der Garabedian B, Lacokova M, Eymard B, Morel E, Faltin M, Zajac J, et al. Association of neonatal myasthenia gravis with antibodies against the fetal acetylcholine receptor. J Clin Invest. 1994;94:555–9.PubMedPubMedCentralCrossRefGoogle Scholar
  196. 196.
    Luo J, Lindstrom J. Antigen-specific immunotherapeutic vaccine for experimental autoimmune myasthenia gravis. J Immunol. 2014;193:5044–55.PubMedPubMedCentralCrossRefGoogle Scholar
  197. 197.
    Lindstrom JM, Lennon VA, Seybold ME, Whittingham S. Experimental autoimmune myasthenia gravis and myasthenia gravis: biochemical and immunochemical aspects. Ann N Y Acad Sci. 1976;274:254–74.Google Scholar
  198. 198.
    Luo J, Lindstrom J. AChR-specific immunosuppressive therapy of myasthenia gravis. Biochem Pharmacol. 2015;97:609–19.PubMedCrossRefGoogle Scholar
  199. 199.
    Willcox N. Thymic tumors with myasthenia gravis or bone marrow dyscrasias. In: Peckham M, Pinedo H, Veronesi U, editors. Oxford textbook of oncology, vol. 1995. Oxford: Oxford University Press; 1995. p. 1562–8.Google Scholar
  200. 200.
    Baggi F, Andreetta F, Antozzi C, Simoncini O, Confalonieri P, Labeit S, et al. Anti-titin and antiryanodine receptor antibodies in myasthenia gravis patients with thymoma. Ann N Y Acad Sci. 1998;841:538–41.PubMedCrossRefGoogle Scholar
  201. 201.
    Cikes N, Momoi MY, Williams CL, Howard FM Jr, Hoagland HC, Whittingham S, et al. Striational autoantibodies: quantitative detection by enzyme immunoassay in myasthenia gravis, thymoma, and recipients of D-penicillamine or allogeneic bone marrow. Mayo Clin Proc. 1988;63:474–81.PubMedCrossRefGoogle Scholar
  202. 202.
    Vincent A, Newsom-Davis J. Acetylcholine receptor antibody characteristics in myasthenia gravis. I. Patients with generalized myasthenia or disease restricted to ocular muscles. Clin Exp Immunol. 1982;49:257–65.PubMedPubMedCentralGoogle Scholar
  203. 203.
    Wakkach A, Guyon T, Bruand C, Tzartos S, Cohen-Kaminsky S, Berrih-Aknin S. Expression of acetylcholine receptor genes in human thymic epithelial cells: implications for myasthenia gravis. J Immunol. 1996;157:3752–60.PubMedGoogle Scholar
  204. 204.
    Zheng Y, Wheatley LM, Liu T, Levinson AI. Acetylcholine receptor α subunit mRNA expression in human thymus: augmented expression in myasthenia gravis and upregulation by interferon-γ. Clin Immunol. 1999;91:170–7.PubMedCrossRefGoogle Scholar
  205. 205.
    Vincent A, Lang B, Newsom-Davis J. Autoimmunity to the voltage-gated calcium channel underlies the Lambert-Eaton myasthenic syndrome, a paraneoplastic disorder. Trends Neurosci. 1989;12:496–502.PubMedCrossRefGoogle Scholar
  206. 206.
    Lindstrom JM, Einarson BL, Lennon VA, Seybold ME. Pathological mechanisms in experimental autoimmune myasthenia gravis. I. Immunogenicity of syngeneic muscle acetylcholine receptor and quantitative extraction of receptor and antibody-receptor complexes from muscles of rats with experimental automimmune myasthenia gravis. J Exp Med. 1976;144:726–38.PubMedCrossRefGoogle Scholar
  207. 207.
    Jermy A, Beeson D, Vincent A. Pathogenic autoimmunity to affinity-purified mouse acetylcholine receptor induced without adjuvant in BALB/c mice. Eur J Immunol. 1993;23:973–6.PubMedCrossRefGoogle Scholar
  208. 208.
    Lindstrom J. Experimental induction and treatment of myasthenia gravis. In: Engel AG, editor. Myasthenia gravis and myasthenic disorders. New York: Oxford University Press; 1999. p. 111–30.Google Scholar
  209. 209.
    Zoda TE, Krolick KA. Antigen presentation and T cell specificity repertoire in determining responsiveness to an epitope important in experimental autoimmune myasthenia gravis. J Neuroimmunol. 1993;43:131–8.PubMedCrossRefGoogle Scholar
  210. 210.
    Lindstrom JM, Seybold ME, Lennon VA, Whittingham S, Duane DD. Antibody to acetylcholine receptor in myasthenia gravis. Prevalence, clinical correlates, and diagnostic value. Neurology. 1976;26:1054–9.PubMedCrossRefGoogle Scholar
  211. 211.
    Sanders DB, Burns TM, Cutter GR, Massey JM, Juel VC, Hobson-Webb L, Muscle Study Group. Does change in acetylcholine receptor antibody level correlate with clinical change in myasthenia gravis? Muscle Nerve. 2014;49:483–6.PubMedCrossRefGoogle Scholar
  212. 212.
    Vincent A, Newsom-Davis J. Acetylcholine receptor antibody as a diagnostic test for myasthenia gravis: results in 153 validated cases and 2967 diagnostic assays. J Neurol Neurosurg Psychiatry. 1985;48:1246–52.PubMedPubMedCentralCrossRefGoogle Scholar
  213. 213.
    Seybold ME, Lindstrom JM. Patterns of acetylcholine receptor antibody fluctuation in myasthenia gravis. Ann N Y Acad Sci. 1981;377:292–306.PubMedCrossRefGoogle Scholar
  214. 214.
    Lindstrom JM, Engel AG, Seybold ME, Lennon VA, Lambert EH. Pathological mechanisms in experimental autoimmune myasthenia gravis. II. Passive transfer of experimental autoimmune myasthenia gravis in rats with anti-acetylcholine recepotr antibodies. J Exp Med. 1976;144:739–53.PubMedCrossRefGoogle Scholar
  215. 215.
    Tzartos S, Hochschwender S, Vasquez P, Lindstrom J. Passive transfer of experimental autoimmune myasthenia gravis by monoclonal antibodies to the main immunogenic region of the acetylcholine receptor. J Neuroimmunol. 1987;15:185–94.PubMedCrossRefGoogle Scholar
  216. 216.
    Toyka KV, Birnberger KL, Anzil AP, Schlegel C, Besinger U, Struppler A. Myasthenia gravis: further electrophysiological and ultrastructural analysis of transmission failure in the mouse passive transfer model. J Neurol Neurosurg Psychiatry. 1978;41:746–53.PubMedPubMedCentralCrossRefGoogle Scholar
  217. 217.
    Toyka KV, Brachman DB, Pestronk A, Kao I. Myasthenia gravis: passive transfer from man to mouse. Science. 1975;190:397–9.PubMedCrossRefGoogle Scholar
  218. 218.
    Engel AG, Sakakibara H, Sahashi K, Lindstrom JM, Lambert EH, Lennon VA. Passively transferred experimental autoimmune myasthenia gravis. Sequential and quantitative study of the motor end-plate fine structure and ultrastructural localization of immune complexes (IgG and C3), and of the acetylcholine receptor. Neurology. 1979;29:179–88.PubMedCrossRefGoogle Scholar
  219. 219.
    Engel AG, Tsujihata M, Lambert EH, Lindstrom JM, Lennon VA. Experimental autoimmune myasthenia gravis: a sequential and quantitative study of the neuromuscular junction ultrastructure and electrophysiologic correlations. J Neuropathol Exp Neurol. 1976;35:569–87.PubMedCrossRefGoogle Scholar
  220. 220.
    Engel AG, Tsujihata M, Lindstrom JM, Lennon VA. The motor end plate in myasthenia gravis and in experimental autoimmune myasthenia gravis. A quantitative ultrastructural study. Ann N Y Acad Sci. 1976;274:60–79.PubMedCrossRefGoogle Scholar
  221. 221.
    Bevan S, Heinemann S, Lennon VA, Lindstrom J. Reduced muscle acetylcholine sensitivity in rats immunised with acetylcholine receptor. Nature. 1976;260:438–9.PubMedCrossRefGoogle Scholar
  222. 222.
    Lambert EH, Lindstrom JM, Lennon VA. End-plate potentials in experimental autoimmune myasthenia gravis in rats. Ann N Y Acad Sci. 1976;274:300–18.PubMedCrossRefGoogle Scholar
  223. 223.
    Lindstrom JM, Lambert EH. Content of acetylcholine receptor and antibodies bound to receptor in myasthenia gravis, experimental autoimmune myasthenia gravis, and Eaton-Lambert syndrome. Neurology. 1978;28:130–8.PubMedCrossRefGoogle Scholar
  224. 224.
    Sahashi K, Engel AG, Lambert EH, Howard FM Jr. Ultrastructural localization of the terminal and lytic ninth complement component (C9) at the motor end-plate in myasthenia gravis. J Neuropathol Exp Neurol. 1980;39:160–72.PubMedCrossRefGoogle Scholar
  225. 225.
    Sahashi K, Engel AG, Linstrom JM, Lambert EH, Lennon VA. Ultrastructural localization of immune complexes (IgG and C3) at the end-plate in experimental autoimmune myasthenia gravis. J Neuropathol Exp Neurol. 1978;37:212–23.PubMedCrossRefGoogle Scholar
  226. 226.
    Appel SH, Anwyl R, McAdams MW, Elias S. Accelerated degradation of acetylcholine receptor from cultured rat myotubes with myasthenia gravis sera and globulins. Proc Natl Acad Sci U S A. 1977;74:2130–4.PubMedPubMedCentralCrossRefGoogle Scholar
  227. 227.
    Bufler J, Pitz R, Czep M, Wick M, Franke C. Purified IgG from seropositive and seronegative patients with mysasthenia gravis reversibly blocks currents through nicotinic acetylcholine receptor channels. Ann Neurol. 1998;43:458–64.PubMedCrossRefGoogle Scholar
  228. 228.
    Burges J, Vincent A, Molenaar PC, Newsom-Davis J, Peers C, Wray D. Passive transfer of seronegative myasthenia gravis to mice. Muscle Nerve. 1994;17:1393–400.PubMedCrossRefGoogle Scholar
  229. 229.
    Donnelly D, Mihovilovic M, Gonzalez-Ros JM, Ferragut JA, Richman D, Martinez-Carrion M. A noncholinergic site-directed monoclonal antibody can impair agonist-induced ion flux in Torpedo californica acetylcholine receptor. Proc Natl Acad Sci U S A. 1984;81:7999–8003.PubMedPubMedCentralCrossRefGoogle Scholar
  230. 230.
    Fels G, Plumer-Wilk R, Schreiber M, Maelicke A. A monoclonal antibody interfering with binding and response of the acetylcholine receptor. J Biol Chem. 1986;261:15746–54.PubMedGoogle Scholar
  231. 231.
    Gomez CM, Richman DP. Anti-acetylcholine receptor antibodies directed against the α-bungarotoxin binding site induce a unique form of experimental myasthenia. Proc Natl Acad Sci U S A. 1983;80:4089–93.PubMedPubMedCentralCrossRefGoogle Scholar
  232. 232.
    Lang B, Richardson G, Rees J, Vincent A, Newsom-Davis J. Plasma from myasthenia gravis patients reduces acetylcholine receptor agonist-induced Na+ flux into TE671 cell line. J Neuroimmunol. 1988;19:141–8.PubMedCrossRefGoogle Scholar
  233. 233.
    Lennon VA, Seybold ME, Lindstrom JM, Cochrane C, Ulevitch R. Role of complement in the pathogenesis of experimental autoimmune myasthenia gravis. J Exp Med. 1978;147:973–83.PubMedCrossRefGoogle Scholar
  234. 234.
    Sine SM, Ohno K, Bouzat C, Auerbach A, Milone M, Pruitt JN, et al. Mutation of the acetylcholine receptor α subunit causes a slow-channel myasthenic syndrome by enhancing agonist binding affinity. Neuron. 1995;15:229–39.PubMedCrossRefGoogle Scholar
  235. 235.
    Ohno K, Wang HL, Milone M, Bren N, Brengman JM, Nakano S, et al. Congenital myasthenic syndrome caused by decreased agonist binding affinity due to a mutation in the acetylcholine receptor ε subunit. Neuron. 1996;17:157–70.PubMedCrossRefGoogle Scholar
  236. 236.
    Shen XM, Brengman JM, Edvardson S, Sine SM, Engel AG. Highly fatal fast-channel syndrome caused by AChR ε subunit mutation at the agonist binding site. Neurology. 2012;79:449–54.PubMedPubMedCentralCrossRefGoogle Scholar
  237. 237.
    Ohno K, Hutchinson DO, Milone M, Brengman JM, Bouzat C, Sine SM, et al. Congenital myasthenic syndrome caused by prolonged acetylcholine receptor channel openings due to a mutation in the M2 domain of the ε subunit. Proc Natl Acad Sci U S A. 1995;92:758–62.PubMedPubMedCentralCrossRefGoogle Scholar
  238. 238.
    Engel AG, Uchitel OD, Walls TJ, Nagel A, Harper CM, Bodensteiner J. Newly recognized congenital myasthenic syndrome associated with high conductance and fast closure of the acetylcholine receptor channel. Ann Neurol. 1993;34:38–47.PubMedCrossRefGoogle Scholar
  239. 239.
    Shen XM, Brengman JM, Sine SM, Engel AG. Myasthenic syndrome AChR α C-loop mutant disrupts initiation of channel gating. J Clin Invest. 2012;122:2613–21.PubMedPubMedCentralCrossRefGoogle Scholar
  240. 240.
    Engel AG. Current status of the congenital myasthenic syndromes. Neuromuscul Disord. 2012;22:99–111.PubMedCrossRefGoogle Scholar
  241. 241.
    Engel AG, Ohno K, Milone M, Wang HL, Nakano S, Bouzat C, et al. New mutations in acetylcholine receptor subunit genes reveal heterogeneity in the slow-channel congenital myasthenic syndrome. Hum Mol Genet. 1996;5:1217–27.PubMedCrossRefGoogle Scholar
  242. 242.
    Ohno K, Anlar B, Engel AG. Congenital myasthenic syndrome caused by a mutation in the Ets-binding site of the promoter region of the acetylcholine receptor ε subunit gene. Neuromuscul Disord. 1999;9:131–5.PubMedCrossRefGoogle Scholar
  243. 243.
    Ohno K, Anlar B, Ozdirim E, Brengman JM, DeBleecker JL, Engel AG. Myasthenic syndromes in Turkish kinships due to mutations in the acetylcholine receptor. Ann Neurol. 1998;44:234–41.PubMedCrossRefGoogle Scholar
  244. 244.
    Ohno K, Quiram PA, Milone M, Wang HL, Harper MC, Pruitt JN II, et al. Congenital myasthenic syndromes due to heteroallelic nonsense/missense mutations in the acetylcholine receptor ε subunit gene: identification and functional characterization of six new mutations. Hum Mol Genet. 1997;6:753–66.PubMedCrossRefGoogle Scholar
  245. 245.
    Missias AC, Mudd J, Cunningham JM, Steinbach JH, Merlie JP, Sanes JR. Deficient development and maintenance of postsynaptic specializations in mutant mice lacking an ‘adult’ acetylcholine receptor subunit. Development. 1997;124:5075–86.PubMedGoogle Scholar
  246. 246.
    Milone M, Wang HL, Ohno K, Fukudome T, Pruitt JN, Bren N, et al. Slow-channel myasthenic syndrome caused by enhanced activation, desensitization, and agonist binding affinity attributable to mutation in the M2 domain of the acetylcholine receptor α subunit. J Neurosci. 1997;17:5651–65.PubMedGoogle Scholar
  247. 247.
    Wang HL, Auerbach A, Bren N, Ohno K, Engel AG, Sine SM. Mutation in the M1 domain of the acetylcholine receptor α subunit decreases the rate of agonist dissociation. J Gen Physiol. 1997;109:757–66.PubMedPubMedCentralCrossRefGoogle Scholar
  248. 248.
    Lo DC, Pinkham JL, Stevens CF. Role of a key cysteine residue in the gating of the acetylcholine receptor. Neuron. 1991;6:31–40.PubMedCrossRefGoogle Scholar
  249. 249.
    Zhou M, Engel AG, Auerbach A. Serum choline activates mutant acetylcholine receptors that cause slow channel congenital myasthenic syndromes. Proc Natl Acad Sci U S A. 1999;96:10466–71.PubMedPubMedCentralCrossRefGoogle Scholar
  250. 250.
    Bertrand D, Devillers-Thiery A, Revah F, Galzi JL, Hussy N, Mulle C, et al. Unconventional pharmacology of a neuronal nicotinic receptor mutated in the channel domain. Proc Natl Acad Sci U S A. 1992;89:1261–5.PubMedPubMedCentralCrossRefGoogle Scholar
  251. 251.
    Alkondon M, Pereira EF, Eisenberg HM, Albuquerque EX. Choline and selective antagonists identify two subtypes of nicotinic acetylcholine receptors that modulate GABA release from CA1 interneurons in rat hippocampal slices. J Neurosci. 1999;19:2693–705.PubMedGoogle Scholar
  252. 252.
    Milone M, Wang HL, Ohno K, Prince R, Fukudome T, Shen XM, et al. Mode switching kinetics produced by a naturally occurring mutation in the cytoplasmic loop of the human acetylcholine receptor ε subunit. Neuron. 1998;20:575–88.PubMedCrossRefGoogle Scholar
  253. 253.
    Han ZY, Le Novere N, Zoli M, Hill JA Jr, Champtiaux N, Changeux JP. Localization of nAChR subunit mRNAs in the brain of Macaca mulatta. Eur J Neurosci. 2000;12:3664–74.PubMedCrossRefGoogle Scholar
  254. 254.
    Vailati S, Moretti M, Balestra B, McIntosh M, Clementi F, Gotti C. β3 subunit is present in different nicotinic receptor subtypes in chick retina. Eur J Pharmacol. 2000;393:23–30.PubMedCrossRefGoogle Scholar
  255. 255.
    Gotti C, Moretti M, Clementi F, Riganti L, McIntosh JM, Collins AC, et al. Expression of nigrostriatal α 6-containing nicotinic acetylcholine receptors is selectively reduced, but not eliminated, by β 3 subunit gene deletion. Mol Pharmacol. 2005;67:2007–15.PubMedCrossRefGoogle Scholar
  256. 256.
    Vailati S, Moretti M, Longhi R, Rovati GE, Clementi F, Gotti C. Developmental expression of heteromeric nicotinic receptor subtypes in chick retina. Mol Pharmacol. 2003;63:1329–37.PubMedCrossRefGoogle Scholar
  257. 257.
    Moretti M, Zoli M, George AA, Lukas RJ, Pistillo F, Maskos U, Whiteaker P, Gotti C. The novel α7β2-nicotinic acetylcholine receptor subtype is expressed in mouse and human basal forebrain: biochemical and pharmacological characterization. Mol Pharmacol. 2014;86:306–17.PubMedPubMedCentralCrossRefGoogle Scholar
  258. 258.
    Thomsen MS, Zwart R, Ursu D, Jensen MM, Pinborg LH, Gilmour G, et al. α7 and β2 Nicotinic acetylcholine receptor subunits form heteromeric receptor complexes that are expressed in the human cortex and display distinct pharmacological properties. PLoS One. 2015;10:e0130572.PubMedPubMedCentralCrossRefGoogle Scholar
  259. 259.
    Wonnacott S. Presynaptic nicotinic ACh receptors. Trends Neurosci. 1997;20:92–8.PubMedCrossRefGoogle Scholar
  260. 260.
    Xu W, Gelber S, Orr-Urtreger A, Armstrong D, Lewis RA, Ou CN, et al. Megacystis, mydriasis, and ion channel defect in mice lacking the α3 neuronal nicotinic acetylcholine receptor. Proc Natl Acad Sci U S A. 1999;96:5746–51.PubMedPubMedCentralCrossRefGoogle Scholar
  261. 261.
    Marubio LM, del Mar Arroyo-Jimenez M, Cordero-Erausquin M, Lena C, Le Novere N, de Kerchove d’Exaerde A, et al. Reduced antinociception in mice lacking neuronal nicotinic receptor subunits. Nature. 1999;398:805–10.PubMedCrossRefGoogle Scholar
  262. 262.
    Ross SA, Wong JY, Clifford JJ, Kinsella A, Massalas JS, Horne MK, et al. Phenotypic characterization of an α 4 neuronal nicotinic acetylcholine receptor subunit knock-out mouse. J Neurosci. 2000;20:6431–41.PubMedGoogle Scholar
  263. 263.
    Labarca C, Schwarz J, Deshpande P, Schwarz S, Nowak MW, Fonck C, Nashmi R, Kofuji P, Dang H, Shi W, Fidan M, Khakh BS, Chen Z, Bowers BJ, Boulter J, Wehner JM, Lester HA. Point mutant mice with hypersensitive α 4 nicotinic receptors show dopaminergic deficits and increased anxiety. Proc Natl Acad Sci U S A. 2001;98:2786–91.PubMedPubMedCentralCrossRefGoogle Scholar
  264. 264.
    Fonck C, Nashmi R, Deshpande P, Damaj MI, Marks MJ, Riedel A, et al. Increased sensitivity to agonist-induced seizures, straub tail, and hippocampal theta rhythm in knock-in mice carrying hypersensitive α 4 nicotinic receptors. J Neurosci. 2003;23:2582–90.PubMedGoogle Scholar
  265. 265.
    Champtiaux N, Gotti C, Cordero-Erausquin M, David DJ, Przybylski C, Lena C, et al. Subunit composition of functional nicotinic receptors in dopaminergic neurons investigated with knock-out mice. J Neurosci. 2003;23:7820–9.PubMedGoogle Scholar
  266. 266.
    Champtiaux N, Han ZY, Bessis A, Rossi FM, Zoli M, Marubio L, et al. Distribution and pharmacology of α 6-containing nicotinic acetylcholine receptors analyzed with mutant mice. J Neurosci. 2002;22:1208–17.PubMedGoogle Scholar
  267. 267.
    Quik M, Vailati S, Bordia T, Kulak JM, Fan H, McIntosh JM, Clementi F, Gotti C. Subunit composition of nicotinic receptors in monkey striatum: effect of treatments with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or L-DOPA. Mol Pharmacol. 2005;67:32–41.PubMedCrossRefGoogle Scholar
  268. 268.
    Franceschini D, Orr-Urtreger A, Yu W, Mackey LY, Bond RA, Armstrong D, et al. Altered baroreflex responses in α7 deficient mice. Behav Brain Res. 2000;113:3–10.PubMedCrossRefGoogle Scholar
  269. 269.
    Orr-Urtreger A, Goldner FM, Saeki M, Lorenzo I, Goldberg L, De Biasi M, et al. Mice deficient in the α7 neuronal nicotinic acetylcholine receptor lack α-bungarotoxin binding sites and hippocampal fast nicotinic currents. J Neurosci. 1997;17:9165–71.PubMedGoogle Scholar
  270. 270.
    Orr-Urtreger A, Broide RS, Kasten MR, Dang H, Dani JA, Beaudet AL, et al. Mice homozygous for the L250T mutation in the α7 nicotinic acetylcholine receptor show increased neuronal apoptosis and die within 1 day of birth. J Neurochem. 2000;74:2154–66.PubMedCrossRefGoogle Scholar
  271. 271.
    Berger F, Gage FH, Vijayaraghavan S. Nicotinic receptor-induced apoptotic cell death of hippocampal progenitor cells. J Neurosci. 1998;18:6871–81.PubMedGoogle Scholar
  272. 272.
    Vetter DE, Liberman MC, Mann J, Barhanin J, Boulter J, Brown MC, et al. Role of α9 nicotinic ACh receptor subunits in the development and function of cochlear efferent innervation. Neuron. 1999;23:93–103.PubMedCrossRefGoogle Scholar
  273. 273.
    Plazas PV, Katz E, Gomez-Casati ME, Bouzat C, Elgoyhen AB. Stoichiometry of the α9α10 nicotinic cholinergic receptor. J Neurosci. 2005;25:10905–12.PubMedCrossRefGoogle Scholar
  274. 274.
    Fuchs PA. Synaptic transmission at vertebrate hair cells. Curr Opin Neurobiol. 1996;6:514–9.PubMedCrossRefGoogle Scholar
  275. 275.
    Maskos U, Molles BE, Pons S, Besson M, Guiard BP, Guilloux JP, et al. Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature. 2005;436:103–7.PubMedCrossRefGoogle Scholar
  276. 276.
    Lena C, Popa D, Grailhe R, Escourrou P, Changeux JP, Adrien J. β2-containing nicotinic receptors contribute to the organization of sleep and regulate putative micro-arousals in mice. J Neurosci. 2004;24:5711–8.Google Scholar
  277. 277.
    Cohen G, Roux JC, Grailhe R, Malcolm G, Changeux JP, Lagercrantz H. Perinatal exposure to nicotine causes deficits associated with a loss of nicotinic receptor function. Proc Natl Acad Sci U S A. 2005;102:3817–21.PubMedPubMedCentralCrossRefGoogle Scholar
  278. 278.
    McCallum SE, Collins AC, Paylor R, Marks MJ. Deletion of the β 2 nicotinic acetylcholine receptor subunit alters development of tolerance to nicotine and eliminates receptor upregulation. Psychopharmacology (Berl). 2006;184:314–27.CrossRefGoogle Scholar
  279. 279.
    Peng X, Gerzanich V, Anand R, Wang F, Lindstrom J. Chronic nicotine treatment up-regulates α3 and α7 acetylcholine receptor subtypes expressed by the human neuroblastoma cell line SH-SY5Y. Mol Pharmacol. 1997;51:776–84.PubMedCrossRefGoogle Scholar
  280. 280.
    Peng X, Gerzanich V, Anand R, Whiting PJ, Lindstrom J. Nicotine-induced increase in neuronal nicotinic receptors results from a decrease in the rate of receptor turnover. Mol Pharmacol. 1994;46:523–30.PubMedGoogle Scholar
  281. 281.
    Wang F, Nelson ME, Kuryatov A, Olale F, Cooper J, Keyser K, et al. Chronic nicotine treatment up-regulates human α3 β2 but not α3 β4 acetylcholine receptors stably transfected in human embryonic kidney cells. J Biol Chem. 1998;273:28721–32.PubMedCrossRefGoogle Scholar
  282. 282.
    Sallette J, Bohler S, Benoit P, Soudant M, Pons S, Le Novere N, et al. An extracellular protein microdomain controls up-regulation of neuronal nicotinic acetylcholine receptors by nicotine. J Biol Chem. 2004;279:18767–75.PubMedCrossRefGoogle Scholar
  283. 283.
    Sallette J, Pons S, Devillers-Thiery A, Soudant M, Prado de Carvalho L, Changeux JP, et al. Nicotine upregulates its own receptors through enhanced intracellular maturation. Neuron. 2005;46:595–607.PubMedCrossRefGoogle Scholar
  284. 284.
    Luther MA, Schoepfer R, Whiting P, Casey B, Blatt Y, Montal MS, et al. A muscle acetylcholine receptor is expressed in the human cerebellar medulloblastoma cell line TE671. J Neurosci. 1989;9:1082–96.PubMedGoogle Scholar
  285. 285.
    Marks MJ, Pauly JR, Gross SD, Deneris ES, Hermans-Borgmeyer I, Heinemann SF, et al. Nicotine binding and nicotinic receptor subunit RNA after chronic nicotine treatment. J Neurosci. 1992;12:2765–84.PubMedGoogle Scholar
  286. 286.
    Perry DC, Davila-Garcia MI, Stockmeier CA, Kellar KJ. Increased nicotinic receptors in brains from smokers: membrane binding and autoradiography studies. J Pharmacol Exp Ther. 1999;289:1545–52.PubMedGoogle Scholar
  287. 287.
    Cui C, Booker TK, Allen RS, Grady SR, Whiteaker P, Marks MJ, et al. The β3 nicotinic receptor subunit: a component of α-conotoxin MII-binding nicotinic acetylcholine receptors that modulate dopamine release and related behaviors. J Neurosci. 2003;23:11045–53.PubMedGoogle Scholar
  288. 288.
    Xu W, Orr-Urtreger A, Nigro F, Gelber S, Sutcliffe CB, Armstrong D, et al. Multiorgan autonomic dysfunction in mice lacking the β2 and the β4 subunits of neuronal nicotinic acetylcholine receptors. J Neurosci. 1999;19:9298–305.PubMedGoogle Scholar
  289. 289.
    Balestra B, Moretti M, Longhi R, Mantegazza R, Clementi F, Gotti C. Antibodies against neuronal nicotinic receptor subtypes in neurological disorders. J Neuroimmunol. 2000;102:89–97.PubMedCrossRefGoogle Scholar
  290. 290.
    Wang Z, Low PA, Vernino S. Antibody-mediated impairment and homeostatic plasticity of autonomic ganglionic synaptic transmission. Exp Neurol. 2010;222:114–9.PubMedPubMedCentralCrossRefGoogle Scholar
  291. 291.
    Wang Z, Low PA, Jordan J, Freeman R, Gibbons CH, Schroeder C, et al. Autoimmune autonomic ganglionopathy: IgG effects on ganglionic acetylcholine receptor current. Neurology. 2007;68:1917–21.PubMedPubMedCentralCrossRefGoogle Scholar
  292. 292.
    Schroeder C, Vernino S, Birkenfeld AL, Tank J, Heusser K, Lipp A, et al. Plasma exchange for primary autoimmune autonomic failure. N Engl J Med. 2005;353:1585–90.PubMedCrossRefGoogle Scholar
  293. 293.
    Lennon VA, Ermilov LG, Szurszewski JH, Vernino S. Immunization with neuronal nicotinic acetylcholine receptor induces neurological autoimmune disease. J Clin Invest. 2003;111:907–13.PubMedPubMedCentralCrossRefGoogle Scholar
  294. 294.
    Vernino S, Low PA, Lennon VA. Experimental autoimmune autonomic neuropathy. J Neurophysiol. 2003;90:2053–9.PubMedCrossRefGoogle Scholar
  295. 295.
    Nguyen VT, Ndoye A, Grando SA. Pemphigus vulgaris antibody identifies pemphaxin. A novel keratinocyte annexin-like molecule binding acetylcholine. J Biol Chem. 2000;275:29466–76.PubMedCrossRefGoogle Scholar
  296. 296.
    Takahashi Y, Mori H, Mishina M, Watanabe M, Kondo N, Shimomura J, et al. Autoantibodies and cell-mediated autoimmunity to NMDA-type GluRε2 in patients with Rasmussen’s encephalitis and chronic progressive epilepsia partialis continua. Epilepsia. 2005;46(Suppl 5):152–8.PubMedCrossRefGoogle Scholar
  297. 297.
    Watson R, Jepson JE, Bermudez I, Alexander S, Hart Y, McKnight K, et al. α7-acetylcholine receptor antibodies in two patients with Rasmussen encephalitis. Neurology. 2005;65:1802–4.PubMedCrossRefGoogle Scholar
  298. 298.
    Dalmau J, Tuzun E, Wu HY, Masjuan J, Rossi JE, Voloschin A, et al. Paraneoplastic anti-N-methyl-D-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol. 2007;61:25–36.PubMedPubMedCentralCrossRefGoogle Scholar
  299. 299.
    Petit-Pedrol M, Armangue T, Peng X, Bataller L, Cellucci T, Davis R, et al. Encephalitis with refractory seizures, status epilepticus, and antibodies to the GABAA receptor: a case series, characterisation of the antigen, and analysis of the effects of antibodies. Lancet Neurol. 2014;13:276–86.Google Scholar
  300. 300.
    Lancaster E, Lai M, Peng X, Hughes E, Constantinescu R, Raizer J, et al. Antibodies to the GABAB receptor in limbic encephalitis with seizures: case series and characterisation of the antigen. Lancet Neurol. 2010;9:67–76.Google Scholar
  301. 301.
    Hutchinson M, Waters P, McHugh J, Gorman G, O’Riordan S, Connolly S, et al. Progressive encephalomyelitis, rigidity, and myoclonus: a novel glycine receptor antibody. Neurology. 2008;71:1291–2.PubMedCrossRefGoogle Scholar
  302. 302.
    Irani SR, Alexander S, Waters P, Kleopa KA, Pettingill P, Zuliani L, et al. Antibodies to Kv1 potassium channel-complex proteins leucine-rich, glioma inactivated 1 protein and contactin-associated protein-2 in limbic encephalitis, Morvan’s syndrome and acquired neuromyotonia. Brain. 2010;133:2734–48.PubMedPubMedCentralCrossRefGoogle Scholar
  303. 303.
    Baker SK, Morillo C, Vernino S. Autoimmune autonomic ganglionopathy with late-onset encephalopathy. Auton Neurosci. 2009;146:29–32.PubMedCrossRefGoogle Scholar
  304. 304.
    De Fusco M, Becchetti A, Patrignani A, Annesi G, Gambardella A, Quattrone A, et al. The nicotinic receptor β2 subunit is mutant in nocturnal frontal lobe epilepsy. Nat Genet. 2000;26:275–6.PubMedCrossRefGoogle Scholar
  305. 305.
    Phillips HA, Favre I, Kirkpatrick M, Zuberi SM, Goudie D, Heron SE, et al. CHRNB2 is the second acetylcholine receptor subunit associated with autosomal dominant nocturnal frontal lobe epilepsy. Am J Hum Genet. 2001;68:225–31.PubMedCrossRefGoogle Scholar
  306. 306.
    Kuryatov A, Gerzanich V, Nelson M, Olale F, Lindstrom J. Mutation causing autosomal dominant nocturnal frontal lobe epilepsy alters Ca2+ permeability, conductance, and gating of human α4β2 nicotinic acetylcholine receptors. J Neurosci. 1997;17:9035–47.PubMedGoogle Scholar
  307. 307.
    Alkondon M, Pereira EF, Eisenberg HM, Albuquerque EX. Nicotinic receptor activation in human cerebral cortical interneurons: a mechanism for inhibition and disinhibition of neuronal networks. J Neurosci. 2000;20:66–75.PubMedGoogle Scholar
  308. 308.
    Rodrigues-Pinguet NO, Pinguet TJ, Figl A, Lester HA, Cohen BN. Mutations linked to autosomal dominant nocturnal frontal lobe epilepsy affect allosteric Ca2+ activation of the α 4 β 2 nicotinic acetylcholine receptor. Mol Pharmacol. 2005;68:487–501.PubMedCrossRefGoogle Scholar
  309. 309.
    Lev-Lehman E, Bercovich D, Xu W, Stockton DW, Beaudet AL. Characterization of the human β4 nAChR gene and polymorphisms in CHRNA3 and CHRNB4. J Hum Genet. 2001;46:362–6.PubMedCrossRefGoogle Scholar
  310. 310.
    Richardson CE, Morgan JM, Jasani B, Green JT, Rhodes J, Williams GT, et al. Megacystis-microcolon-intestinal hypoperistalsis syndrome and the absence of the α3 nicotinic acetylcholine receptor subunit. Gastroenterology. 2001;121:350–7.PubMedCrossRefGoogle Scholar
  311. 311.
    Sabatelli M, Eusebi F, Al-Chalabi A, Conte A, Madia F, Luigetti M, et al. Rare missense variants of neuronal nicotinic acetylcholine receptor altering receptor function are associated with sporadic amyotrophic lateral sclerosis. Hum Mol Genet. 2009;18:3997–4006.PubMedCrossRefGoogle Scholar

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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Clinical Sciences and Advanced MedicineUniversity of Pennsylvania School of Veterinary MedicinePhiladelphiaUSA
  2. 2.Department of NeuroscienceMedical School of the University of PennsylvaniaPhiladelphiaUSA

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