Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system

Key Points

  • The nicotinic acetylcholine receptors (nAChRs) are the most well understood membrane receptors for neurotransmitters at the structural and functional level. They are integral allosteric membrane proteins comprising five identical or homologous subunits symmetrically arranged around a central ionic channel.

  • The acetylcholine (ACh)-binding sites on the nAChR are located in the extracellular domain at subunit boundaries, and their structure and drug selectivity is being elucidated at the atomic level. The structure of the ion channel in its potentially open and closed conformations and the site for channel blockers are known from studies on bacterial homologues.

  • Structural and molecular modelling studies support the model of a global quaternary twist motion for the conformational transition that links the ACh-binding site and the ion channel.

  • Several categories of sites of action for allosteric modulators are being identified.

  • nAChRs are the focus of intense drug discovery efforts for the treatment of several nervous-system disorders, including Alzheimer's disease, Parkinson's disease, schizophrenia, depression and attention deficit hyperactivity disorder, as well as for pain and smoking cessation.

  • The aim of this article is to illustrate the possible benefits to drug design efforts of orthosteric and allosteric ligands that are emerging from the present understanding of the atomic structure, functional organization and conformational transitions of nAChRs, in the attempt to bridge the gap between these two fields of research.

Abstract

Nicotinic receptors — a family of ligand-gated ion channels that mediate the effects of the neurotransmitter acetylcholine — are among the most well understood allosteric membrane proteins from a structural and functional perspective. There is also considerable interest in modulating nicotinic receptors to treat nervous-system disorders such as Alzheimer's disease, schizophrenia, depression, attention deficit hyperactivity disorder and tobacco addiction. This article describes both recent advances in our understanding of the assembly, activity and conformational transitions of nicotinic receptors, as well as developments in the therapeutic application of nicotinic receptor ligands, with the aim of aiding novel drug discovery by bridging the gap between these two rapidly developing fields.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Variability of nicotinic binding sites and receptor subunits.
Figure 2: Model of the α7 nicotinic acetylcholine receptor (nAChR).
Figure 3: Structure of the acetylcholine (ACh)-binding site on the α7 nicotinic acetylcholine receptor (nAChR).
Figure 4: Potential binding sites for allosteric modulators.
Figure 5: The nAChR gating mechanism.

Similar content being viewed by others

References

  1. Changeux, J. P. & Edelstein, S. J. Allosteric mechanisms of signal transduction. Science 308, 1424–1428 (2005).

    CAS  PubMed  Google Scholar 

  2. Corringer, P. J., Le Novere, N. & Changeux, J. P. Nicotinic receptors at the amino acid level. Annu. Rev. Pharmacol. Toxicol. 40, 431–458 (2000).

    CAS  PubMed  Google Scholar 

  3. 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. USA 98, 1241–1248 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Sine, S. M. & Engel, A. G. Recent advances in Cys-loop receptor structure and function. Nature 440, 448–455 (2006).

    CAS  PubMed  Google Scholar 

  5. Changeux, J. P. & Edelstein, S. J. Nicotinic Acetylcholine Receptors: From Molecular Biology To Cognition (Odile Jacob, New York, 2005). A general review book on nicotinic receptors and their function.

    Google Scholar 

  6. Gotti, C., Riganti, L., Vailati, S. & Clementi, F. Brain neuronal nicotinic receptors as new targets for drug discovery. Curr. Pharm. Des. 12, 407–428 (2006).

    CAS  PubMed  Google Scholar 

  7. Dani, J. A. & Bertrand, D. Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system. Annu. Rev. Pharmacol. Toxicol. 47, 699–729 (2007).

    CAS  PubMed  Google Scholar 

  8. Sallette, J. et al. Nicotine upregulates its own receptors through enhanced intracellular maturation. Neuron 46, 595–607 (2005).

    CAS  PubMed  Google Scholar 

  9. Arneric, S. P., Holladay, M. & Williams, M. Neuronal nicotinic receptors: a perspective on two decades of drug discovery research. Biochem. Pharmacol. 74, 1092–1101 (2007). An historical account and outlook on future research on nicotinic compounds in the pharmaceutical industry.

    CAS  PubMed  Google Scholar 

  10. Levin, E. D. & Rezvani, A. H. Nicotinic interactions with antipsychotic drugs, models of schizophrenia and impacts on cognitive function. Biochem. Pharmacol. 74, 1182–1191 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Romanelli, M. N. et al. Central nicotinic receptors: structure, function, ligands, and therapeutic potential. ChemMedChem 2, 746–767 (2007).

    CAS  PubMed  Google Scholar 

  12. Changeux, J. P. & Taly, A. Nicotinic receptors, allosteric proteins and medicine. Trends Mol. Med. 14, 93–102 (2008).

    CAS  PubMed  Google Scholar 

  13. Gotti, C. et al. Heterogeneity and complexity of native brain nicotinic receptors. Biochem. Pharmacol. 74, 1102–1111 (2007).

    CAS  PubMed  Google Scholar 

  14. Grady, S. R. et al. Rodent habenulo-interpeduncular pathway expresses a large variety of uncommon nAChR subtypes, but only the α3β4* and α3β3β4* subtypes mediate acetylcholine release. J. Neurosci. 29, 2272–2282 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Brejc, K. et al. Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature 411, 269–276 (2001). This paper describes the first-characterized atomic structure of an invertebrate homologue of the extracellular domain and ACh-binding sites of the nAChR.

    CAS  PubMed  Google Scholar 

  16. Celie, P. H. et al. Crystal structure of acetylcholine-binding protein from Bulinus truncatus reveals the conserved structural scaffold and sites of variation in nicotinic acetylcholine receptors. J. Biol. Chem. 280, 26457–26466 (2005).

    CAS  PubMed  Google Scholar 

  17. Hansen, S. B. et al. Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations. EMBO J. 24, 3635–3646 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Corringer, P. J. et al. Identification of a new component of the agonist binding site of the nicotinic α7 homooligomeric receptor. J. Biol. Chem. 270, 11749–11752 (1995).

    CAS  PubMed  Google Scholar 

  19. Grutter, T. & Changeux, J. P. Nicotinic receptors in wonderland. Trends Biochem. Sci. 26, 459–463 (2001).

    CAS  PubMed  Google Scholar 

  20. Mourot, A., Grutter, T., Goeldner, M. & Kotzyba-Hibert, F. Dynamic structural investigations on the torpedo nicotinic acetylcholine receptor by time-resolved photoaffinity labeling. Chembiochem 7, 570–583 (2006).

    CAS  PubMed  Google Scholar 

  21. Sine, S. M. The nicotinic receptor ligand binding domain. J. Neurobiol. 53, 431–446 (2002).

    CAS  PubMed  Google Scholar 

  22. Kotzyba-Hibert, F., Mourot, A., Grutter, T. & Goeldner, M. in XIth Cholinergic Mechanisms Symposium (eds. Fisher, M. D. L. A. & Soreq, H.) 607 (Taylor & Francis, London, 2004).

    Google Scholar 

  23. Kalamida, D. et al. Muscle and neuronal nicotinic acetylcholine receptors. Structure, function and pathogenicity. FEBS J. 274, 3799–3845 (2007).

    CAS  PubMed  Google Scholar 

  24. Bourne, Y., Talley, T. T., Hansen, S. B., Taylor, P. & Marchot, P. Crystal structure of a Cbtx-AChBP complex reveals essential interactions between snake α-neurotoxins and nicotinic receptors. EMBO J. 24, 1512–1522 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Brejc, K., van Dijk, W. J., Smit, A. B. & Sixma, T. K. The 2.7 Å structure of AChBP, homologue of the ligand-binding domain of the nicotinic acetylcholine receptor. Novartis Found. Symp. 245, 22–29; discussion 29–32, 165–8 (2002).

    CAS  PubMed  Google Scholar 

  26. Celie, P. H. et al. Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures. Neuron 41, 907–914 (2004).

    CAS  PubMed  Google Scholar 

  27. Celie, P. H. et al. Crystal structure of nicotinic acetylcholine receptor homolog AChBP in complex with an α-conotoxin PnIA variant. Nature Struct. Mol. Biol. 12, 582–588 (2005).

    CAS  Google Scholar 

  28. Hansen, S. B. et al. Structural characterization of agonist and antagonist-bound acetylcholine-binding protein from Aplysia californica. J. Mol. Neurosci. 30, 101–102 (2006). This study describes the structure of the ligand-binding domain of AChBP bound to several nicotinic agonists and antagonists.

    CAS  PubMed  Google Scholar 

  29. Hansen, S. B. & Taylor, P. Galanthamine and non-competitive inhibitor binding to ACh-binding protein: evidence for a binding site on non-α-subunit interfaces of heteromeric neuronal nicotinic receptors. J. Mol. Biol. 369, 895–901 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Ihara, M. et al. Crystal structures of Lymnaea stagnalis AChBP in complex with neonicotinoid insecticides imidacloprid and clothianidin. Invert. Neurosci. 8, 71–81 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Dennis, M. et al. Amino acids of the Torpedo marmorata acetylcholine receptor alpha subunit labeled by a photoaffinity ligand for the acetylcholine binding site. Biochemistry 27, 2346–2357 (1988).

    CAS  PubMed  Google Scholar 

  32. Galzi, J. L. et al. Identification of a novel amino acid α-tyrosine 93 within the cholinergic ligands-binding sites of the acetylcholine receptor by photoaffinity labeling. Additional evidence for a three-loop model of the cholinergic ligands-binding sites. J. Biol. Chem. 265, 10430–10437 (1990).

    CAS  PubMed  Google Scholar 

  33. Zhong, W. et al. From ab initio quantum mechanics to molecular neurobiology: a cation-π binding site in the nicotinic receptor. Proc. Natl Acad. Sci. USA 95, 12088–12093 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Xiu, X., Puskar, N. L., Shanata, J. A., Lester, H. A. & Dougherty, D. A. Nicotine binding to brain receptors requires a strong cation-π interaction. Nature 458, 534–537 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Williamson, P. T., Verhoeven, A., Miller, K. W., Meier, B. H. & Watts, A. The conformation of acetylcholine at its target site in the membrane-embedded nicotinic acetylcholine receptor. Proc. Natl Acad. Sci. USA 104, 18031–18036 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Ulens, C. et al. Structural determinants of selective α-conotoxin binding to a nicotinic acetylcholine receptor homolog AChBP. Proc. Natl Acad. Sci. USA 103, 3615–3620 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Yuan, H. & Petukhov, P. A. Computational evidence for the ligand selectivity to the α4β2 and α3β4 nicotinic acetylcholine receptors. Bioorg. Med. Chem. 14, 7936–7942 (2006).

    CAS  PubMed  Google Scholar 

  38. Corringer, P. J. et al. Critical elements determining diversity in agonist binding and desensitization of neuronal nicotinic acetylcholine receptors. J. Neurosci. 18, 648–657 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Horenstein, N. A., McCormack, T. J., Stokes, C., Ren, K. & Papke, R. L. Reversal of agonist selectivity by mutations of conserved amino acids in the binding site of nicotinic acetylcholine receptors. J. Biol. Chem. 282, 5899–5909 (2007).

    CAS  PubMed  Google Scholar 

  40. Dutertre, S. & Lewis, R. J. Toxin insights into nicotinic acetylcholine receptors. Biochem. Pharmacol. 72, 661–670 (2006).

    CAS  PubMed  Google Scholar 

  41. Grutter, T. et al. A chimera encoding the fusion of an acetylcholine-binding protein to an ion channel is stabilized in a state close to the desensitized form of ligand-gated ion channels. C. R. Biol. 328, 223–234 (2005).

    CAS  PubMed  Google Scholar 

  42. Giraudat, J., Dennis, M., Heidmann, T., Chang, J. Y. & Changeux, J. P. Structure of the high-affinity binding site for noncompetitive blockers of the acetylcholine receptor: serine-262 of the δ subunit is labeled by [3H]chlorpromazine. Proc. Natl Acad. Sci. USA 83, 2719–2723 (1986).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Blanton, M. P., McCardy, E. A., Huggins, A. & Parikh, D. Probing the structure of the nicotinic acetylcholine receptor with the hydrophobic photoreactive probes [125I]TID-BE and [125I]TIDPC/16. Biochemistry 37, 14545–14555 (1998).

    CAS  PubMed  Google Scholar 

  44. Faghih, R., Gopalakrishnan, M. & Briggs, C. A. Allosteric modulators of the α7 nicotinic acetylcholine receptor. J. Med. Chem. 51, 701–712 (2008).

    CAS  PubMed  Google Scholar 

  45. Bertrand, D. & Gopalakrishnan, M. Allosteric modulation of nicotinic acetylcholine receptors. Biochem. Pharmacol. 74, 1155–1163 (2007).

    CAS  PubMed  Google Scholar 

  46. Arias, H. R., Bhumireddy, P. & Bouzat, C. Molecular mechanisms and binding site locations for noncompetitive antagonists of nicotinic acetylcholine receptors. Int. J. Biochem. Cell Biol. 38, 1254–1276 (2006).

    CAS  PubMed  Google Scholar 

  47. Hsiao, B. et al. Determinants of zinc potentiation on the α4 subunit of neuronal nicotinic receptors. Mol. Pharmacol. 69, 27–36 (2006).

    CAS  PubMed  Google Scholar 

  48. Moroni, M. et al. Non-agonist-binding subunit interfaces confer distinct functional signatures to the alternate stoichiometries of the α4β2 nicotinic receptor: an α4–α4 interface is required for Zn2+ potentiation. J. Neurosci. 28, 6884–6894 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Sigel, E. Mapping of the benzodiazepine recognition site on GABAA receptors. Curr. Top. Med. Chem. 2, 833–839 (2002).

    CAS  PubMed  Google Scholar 

  50. Galzi, J. L., Bertrand, S., Corringer, P. J., Changeux, J. P. & Bertrand, D. Identification of calcium binding sites that regulate potentiation of a neuronal nicotinic acetylcholine receptor. EMBO J. 15, 5824–5832 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Le Novere, N., Grutter, T. & Changeux, J. P. Models of the extracellular domain of the nicotinic receptors and of agonist- and Ca2+-binding sites. Proc. Natl Acad. Sci. USA 99, 3210–3215 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. McLaughlin, J. T., Fu, J., Sproul, A. D. & Rosenberg, R. L. Role of the outer β-sheet in divalent cation modulation of α7 nicotinic receptors. Mol. Pharmacol. 70, 16–22 (2006).

    CAS  PubMed  Google Scholar 

  53. Bocquet, N. et al. X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation. Nature 457, 111–114 (2009). This paper, together with reference 80, provided the first-characterized atomic structure of a bacterial channel in an apparently open conformation, constituting atomic resolution of a possible gating mechanism.

    CAS  PubMed  Google Scholar 

  54. Popot, J. L., Demel, R. A., Sobel, A., Van Deenen, L. L. & Changeux, J. P. Interaction of the acetylcholine (nicotinic) receptor protein from Torpedo marmorata electric organ with monolayers of pure lipids. Eur. J. Biochem. 85, 27–42 (1978).

    CAS  PubMed  Google Scholar 

  55. Barrantes, F. J. Structural basis for lipid modulation of nicotinic acetylcholine receptor function. Brain Res. Brain Res. Rev. 47, 71–95 (2004).

    CAS  PubMed  Google Scholar 

  56. Dacosta, C. J. & Baenziger, J. E. A lipid-dependent uncoupled conformation of the acetylcholine receptor. J. Biol. Chem. 284, 17819–17825 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Hamouda, A. K., Chiara, D. C., Sauls, D., Cohen, J. B. & Blanton, M. P. Cholesterol interacts with transmembrane α-helices M1, M3, and M4 of the Torpedo nicotinic acetylcholine receptor: photolabeling studies using [3H]azicholesterol. Biochemistry 45, 976–986 (2006).

    CAS  PubMed  Google Scholar 

  58. Blanton, M. P., Xie, Y., Dangott, L. J. & Cohen, J. B. The steroid promegestone is a noncompetitive antagonist of the Torpedo nicotinic acetylcholine receptor that interacts with the lipid–protein interface. Mol. Pharmacol. 55, 269–278 (1999).

    CAS  PubMed  Google Scholar 

  59. Nievas, G. A., Barrantes, F. J. & Antollini, S. S. Conformation-sensitive steroid and fatty acid sites in the transmembrane domain of the nicotinic acetylcholine receptor. Biochemistry 46, 3503–3512 (2007).

    PubMed  Google Scholar 

  60. Hosie, A. M., Buckingham, S. D., Hamon, A. & Sattelle, D. B. Replacement of asparagine with arginine at the extracellular end of the second transmembrane (M2) region of insect GABA receptors increases sensitivity to penicillin G. Invert. Neurosci. 6, 75–79 (2006).

    CAS  PubMed  Google Scholar 

  61. Nirthanan, S., Garcia, G. III, Chiara, D. C., Husain, S. S. & Cohen, J. B. Identification of binding sites in the nicotinic acetylcholine receptor for TDBzl-etomidate, a photoreactive positive allosteric effector. J. Biol. Chem. 283, 22051–22062 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Chiara, D. C., Dangott, L. J., Eckenhoff, R. G. & Cohen, J. B. Identification of nicotinic acetylcholine receptor amino acids photolabeled by the volatile anesthetic halotane. Biochemistry 42, 13457–13467 (2003).

    CAS  PubMed  Google Scholar 

  63. Young, G. T., Zwart, R., Walker, A. S., Sher, E. & Millar, N. S. Potentiation of α7 nicotinic acetylcholine receptors via an allosteric transmembrane site. Proc. Natl Acad. Sci. USA 105, 14686–14691 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Bertrand, D. et al. Positive allosteric modulation of the α7 nicotinic acetylcholine receptor: ligand interactions with distinct binding sites and evidence for a prominent role of the M2–M3 segment. Mol. Pharmacol. 74, 1407–1416 (2008). This study and reference 63 report the first identification of the binding site for allosteric modulators in the transmembrane domain of nAChRs.

    CAS  PubMed  Google Scholar 

  65. Li, G. D. et al. Identification of a GABAA receptor anesthetic binding site at subunit interfaces by photolabeling with an etomidate analog. J. Neurosci. 26, 11599–11605 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Hales, T. G. 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. 281, 8062–8071 (2006).

    CAS  PubMed  Google Scholar 

  67. Swope, S. L., Qu, Z. & Huganir, R. L. Phosphorylation of the nicotinic acetylcholine receptor by protein tyrosine kinases. Ann. NY Acad. Sci. 757, 197–214 (1995).

    CAS  PubMed  Google Scholar 

  68. Lee, Y. et al. Rapsyn carboxyl terminal domains mediate muscle specific kinase-induced phosphorylation of the muscle acetylcholine receptor. Neuroscience 153, 997–1007 (2008).

    CAS  PubMed  Google Scholar 

  69. Lin, L. et al. The calcium sensor protein visinin-like protein-1 modulates the surface expression and agonist sensitivity of the α4β2 nicotinic acetylcholine receptor. J. Biol. Chem. 277, 41872–41878 (2002).

    CAS  PubMed  Google Scholar 

  70. Kabbani, N., Woll, M. P., Levenson, R., Lindstrom, J. M. & Changeux, J. P. Intracellular complexes of the β2 subunit of the nicotinic acetylcholine receptor in brain identified by proteomics. Proc. Natl Acad. Sci. USA 104, 20570–20575 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Unwin, N., Miyazawa, A., Li, J. & Fujiyoshi, Y. Activation of the nicotinic acetylcholine receptor involves a switch in conformation of the α subunits. J. Mol. Biol. 319, 1165–1176 (2002).

    CAS  PubMed  Google Scholar 

  72. Krebs, W. G. et al. Normal mode analysis of macromolecular motions in a database framework: developing mode concentration as a useful classifying statistic. Proteins 48, 682–695 (2002).

    CAS  PubMed  Google Scholar 

  73. Bahar, I. & Rader, A. J. Coarse-grained normal mode analysis in structural biology. Curr. Opin. Struct. Biol. 15, 586–592 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Taly, A. et al. Normal mode analysis suggests a quaternary twist model for the nicotinic receptor gating mechanism. Biophys. J. 88, 3954–3965 (2005). The first proposal of a gating mechanism of the nAChR channel by a quaternary twist mechanism.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Taly, A. et al. Implications of the quaternary twist allosteric model for the physiology and pathology of nicotinic acetylcholine receptors. Proc. Natl Acad. Sci. USA 103, 16965–16970 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Taly, A. Opened by a twist: a gating mechanism for the nicotinic acetylcholine receptor. Eur. Biophys. J. 36, 911–918 (2007).

    PubMed  Google Scholar 

  77. Konstantakaki, M., Changeux, J. & Taly, A. Docking of long chain α-cobratoxin suggests a basal state conformation of the nicotinic receptor. Biochem. Biophys. Res. Commun. 359, 413–418 (2007).

    CAS  PubMed  Google Scholar 

  78. Samson, A. O. & Levitt, M. Inhibition mechanism of the acetylcholine receptor by α-neurotoxins as revealed by normal-mode dynamics. Biochemistry 47, 4065–4070 (2008).

    CAS  PubMed  Google Scholar 

  79. Yi, M., Tjong, H. & Zhou, H. X. Spontaneous conformational change and toxin binding in α7 acetylcholine receptor: insight into channel activation and inhibition. Proc. Natl Acad. Sci. USA 105, 8280–8285 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Hilf, R. J. & Dutzler, R. Structure of a potentially open state of a proton-activated pentameric ligand-gated ion channel. Nature 457, 115–118 (2009).

    CAS  PubMed  Google Scholar 

  81. Hilf, R. J. & Dutzler, R. X-ray structure of a prokaryotic pentameric ligand-gated ion channel. Nature 452, 375–379 (2008). The first crystallographic structure to be resolved of a bacterial receptor channel that is homologous to nicotinic receptors.

    CAS  PubMed  Google Scholar 

  82. Bocquet, N. et al. A prokaryotic proton-gated ion channel from the nicotinic acetylcholine receptor family. Nature 445, 116–119 (2007). The first demonstration of a functional bacterial receptor channel that is homologous to nicotinic receptors.

    CAS  PubMed  Google Scholar 

  83. Fruchart-Gaillard, C. et al. Experimentally based model of a complex between a snake toxin and the α7 nicotinic receptor. Proc. Natl Acad. Sci. USA 99, 3216–3221 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Lyukmanova, E. N. et al. Bacterial expression, NMR, and electrophysiology analysis of chimeric short/long-chain α-neurotoxins acting on neuronal nicotinic receptors. J. Biol. Chem. 282, 24784–24791 (2007).

    CAS  PubMed  Google Scholar 

  85. Gay, E. A., Bienstock, R. J., Lamb, P. W. & Yakel, J. L. Structural determinates for apolipoprotein E-derived peptide interaction with the α7 nicotinic acetylcholine receptor. Mol. Pharmacol. 72, 838–849 (2007).

    CAS  PubMed  Google Scholar 

  86. Mordvitsev, D. Y. et al. Computer modeling of binding of diverse weak toxins to nicotinic acetylcholine receptors. Comput. Biol. Chem. 31, 72–81 (2007).

    CAS  PubMed  Google Scholar 

  87. Huang, X. et al. Modeling subtype-selective agonists binding with α4β2 and α7 nicotinic acetylcholine receptors: effects of local binding and long-range electrostatic interactions. J. Med. Chem. 49, 7661–7674 (2006).

    CAS  PubMed  Google Scholar 

  88. Mordvintsev, D. Y. et al. A model for short α-neurotoxin bound to nicotinic acetylcholine receptor from Torpedo californica: comparison with long-chain α-neurotoxins and α-conotoxins. Comput. Biol. Chem. 29, 398–411 (2005).

    CAS  PubMed  Google Scholar 

  89. Dutertre, S. & Lewis, R. J. Computational approaches to understand α-conotoxin interactions at neuronal nicotinic receptors. Eur. J. Biochem. 271, 2327–2334 (2004).

    CAS  PubMed  Google Scholar 

  90. Dutertre, S., Nicke, A., Tyndall, J. D. & Lewis, R. J. Determination of α-conotoxin binding modes on neuronal nicotinic acetylcholine receptors. J. Mol. Recognit. 17, 339–347 (2004).

    CAS  PubMed  Google Scholar 

  91. Jozwiak, K., Ravichandran, S., Collins, J. R. & Wainer, I. W. Interaction of noncompetitive inhibitors with an immobilized α3β4 nicotinic acetylcholine receptor investigated by affinity chromatography, quantitative-structure activity relationship analysis, and molecular docking. J. Med. Chem. 47, 4008–4021 (2004).

    CAS  PubMed  Google Scholar 

  92. Dutertre, S., Nicke, A. & Lewis, R. J. β2 subunit contribution to 4/7 α-conotoxin binding to the nicotinic acetylcholine receptor. J. Biol. Chem. 280, 30460–30468 (2005).

    CAS  PubMed  Google Scholar 

  93. Ellison, M. et al. α-conotoxins ImI and ImII target distinct regions of the human α7 nicotinic acetylcholine receptor and distinguish human nicotinic receptor subtypes. Biochemistry 43, 16019–16026 (2004).

    CAS  PubMed  Google Scholar 

  94. Jin, A. H. et al. Molecular engineering of conotoxins: the importance of loop size to α-conotoxin structure and function. J. Med. Chem. 51, 5575–5584 (2008).

    CAS  PubMed  Google Scholar 

  95. Konstantakaki, M., Tzartos, S. J., Poulas, K. & Eliopoulos, E. Model of the extracellular domain of the human α7 nAChR based on the crystal structure of the mouse α1 nAChR extracellular domain. J. Mol. Graph. Model 26, 1333–1337 (2008).

    CAS  PubMed  Google Scholar 

  96. Rocher, A. & Marchand-Geneste, N. Homology modelling of the Apis mellifera nicotinic acetylcholine receptor (nAChR) and docking of imidacloprid and fipronil insecticides and their metabolites. SAR QSAR Environ. Res. 19, 245–261 (2008).

    CAS  PubMed  Google Scholar 

  97. Huang, X., Zheng, F., Crooks, P. A., Dwoskin, L. P. & Zhan, C. G. Modeling multiple species of nicotine and deschloroepibatidine interacting with α4β2 nicotinic acetylcholine receptor: from microscopic binding to phenomenological binding affinity. J. Am. Chem. Soc. 127, 14401–14414 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Artali, R., Bombieri, G. & Meneghetti, F. Docking of 6-chloropyridazin-3-yl derivatives active on nicotinic acetylcholine receptors into molluscan acetylcholine binding protein (AChBP). Farmaco 60, 313–320 (2005).

    CAS  PubMed  Google Scholar 

  99. Bisson, W. H., Scapozza, L., Westera, G., Mu, L. & Schubiger, P. A. Ligand selectivity for the acetylcholine binding site of the rat α4β2 and α3β4 nicotinic subtypes investigated by molecular docking. J. Med. Chem. 48, 5123–5130 (2005).

    CAS  PubMed  Google Scholar 

  100. Costa, V., Nistri, A., Cavalli, A. & Carloni, P. A structural model of agonist binding to the α3β4 neuronal nicotinic receptor. Br. J. Pharmacol. 140, 921–931 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Han, Z. Y. et al. Localization of nAChR subunit mRNAs in the brain of Macaca mulatta. Eur. J. Neurosci. 12, 3664–3674 (2000).

    CAS  PubMed  Google Scholar 

  102. Han, Z. Y. et al. Localization of [3H]nicotine, [3H]cytisine, [3H]epibatidine, and [125I]α-bungarotoxin binding sites in the brain of Macaca mulatta. J. Comp. Neurol. 461, 49–60 (2003). An extensive analysis of the distribution of the various nicotinic binding sites in a primate brain.

    CAS  PubMed  Google Scholar 

  103. Nelson, M. E., Kuryatov, A., Choi, C. H., Zhou, Y. & Lindstrom, J. Alternate stoichiometries of α4β2 nicotinic acetylcholine receptors. Mol. Pharmacol. 63, 332–341 (2003).

    CAS  PubMed  Google Scholar 

  104. Buisson, B. & Bertrand, D. Chronic exposure to nicotine upregulates the human α4β2 nicotinic acetylcholine receptor function. J. Neurosci. 21, 1819–1829 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Champtiaux, N. et al. Distribution and pharmacology of α6-containing nicotinic acetylcholine receptors analyzed with mutant mice. J. Neurosci. 22, 1208–1217 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Grady, S. R. et al. The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum. Biochem. Pharmacol. 74, 1235–1246 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Salas, R., Sturm, R., Boulter, J. & De Biasi, M. Nicotinic receptors in the habenulo-interpeduncular system are necessary for nicotine withdrawal in mice. J. Neurosci. 29, 3014–3018 (2009). A clear demonstration of the contribution of structural nAChR subunits to nicotine withdrawal symptoms.

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Taylor, P. et al. Structure-guided drug design: conferring selectivity among neuronal nicotinic receptor and acetylcholine-binding protein subtypes. Biochem. Pharmacol. 74, 1164–1171 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Huang, X., Zheng, F., Stokes, C., Papke, R. L. & Zhan, C. G. Modeling binding modes of α7 nicotinic acetylcholine receptor with ligands: the roles of Gln117 and other residues of the receptor in agonist binding. J. Med. Chem. 51, 6293–6302 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Grosman, C. & Auerbach, A. Kinetic, mechanistic, and structural aspects of unliganded gating of acetylcholine receptor channels: a single-channel study of second transmembrane segment 12′ mutants. J. Gen. Physiol. 115, 621–635 (2000). An extensive single-channel analysis of the nAChR gating mechanism, using mutagenesis studies.

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Lange, O. F. et al. Recognition dynamics up to microseconds revealed from an RDC-derived ubiquitin ensemble in solution. Science 320, 1471–1475 (2008).

    CAS  PubMed  Google Scholar 

  112. Tobi, D. & Bahar, I. Structural changes involved in protein binding correlate with intrinsic motions of proteins in the unbound state. Proc. Natl Acad. Sci. USA 102, 18908–18913 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Engel, A. G., Ohno, K. & Sine, S. M. Congenital myasthenic syndromes: a diverse array of molecular targets. J. Neurocytol. 32, 1017–1037 (2003).

    CAS  PubMed  Google Scholar 

  114. Cheng, X., Wang, H., Grant, B., Sine, S. M. & McCammon, J. A. Targeted molecular dynamics study of C-loop closure and channel gating in nicotinic receptors. PLoS Comput. Biol. 2, e134 (2006).

    PubMed  PubMed Central  Google Scholar 

  115. Haddadian, E. J., Cheng, M. H., Coalson, R. D., Xu, Y. & Tang, P. In silico models for the human α4β2 nicotinic acetylcholine receptor. J. Phys. Chem. B 112, 13981–13990 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Rubin, M. M. & Changeux, J. P. On the nature of allosteric transitions: implications of non-exclusive ligand binding. J. Mol. Biol. 21, 265–274 (1966).

    CAS  PubMed  Google Scholar 

  117. Marshall, C. G., Ogden, D. C. & Colquhoun, D. The actions of suxamethonium (succinyldicholine) as an agonist and channel blocker at the nicotinic receptor of frog muscle. J. Physiol. 428, 155–174 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Lape, R., Colquhoun, D. & Sivilotti, L. G. On the nature of partial agonism in the nicotinic receptor superfamily. Nature 454, 722–727 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Mukhtasimova, N., Lee, W. Y., Wang, H. L. & Sine, S. M. Detection and trapping of intermediate states priming nicotinic receptor channel opening. Nature 459, 451–454 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Buccafusco, J. J., Beach, J. W. & Terry, A. V. Jr. Desensitization of nicotinic acetylcholine receptors as a strategy for drug development. J. Pharmacol. Exp. Ther. 328, 364–370 (2009).

    CAS  PubMed  Google Scholar 

  121. Schuller, H. M. Is cancer triggered by altered signalling of nicotinic acetylcholine receptors? Nature Rev. Cancer 9, 195–205 (2009).

    CAS  Google Scholar 

  122. Lefkowitz, R. J., Rajagopal, K. & Whalen, E. J. New roles for β-arrestins in cell signaling: not just for seven-transmembrane receptors. Mol. Cell 24, 643–652 (2006).

    CAS  PubMed  Google Scholar 

  123. Kihara, T. et al. α7 nicotinic receptor transduces signals to phosphatidylinositol 3-kinase to block Aβ-amyloid-induced neurotoxicity. J. Biol. Chem. 276, 13541–13546 (2001).

    CAS  PubMed  Google Scholar 

  124. Buckingham, S. D., Jones, A. K., Brown, L. A. & Sattelle, D. B. Nicotinic acetylcholine receptor signalling: roles in Alzheimer's disease and amyloid neuroprotection. Pharmacol. Rev. 61, 39–61 (2009). A detailed analysis of nicotinic neuroprotection against amyloid-β toxicity.

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Miwa, J. M. et al. The prototoxin lynx1 acts on nicotinic acetylcholine receptors to balance neuronal activity and survival in vivo. Neuron 51, 587–600 (2006).

    CAS  PubMed  Google Scholar 

  126. Kasa, P., Rakonczay, Z. & Gulya, K. The cholinergic system in Alzheimer's disease. Prog. Neurobiol. 52, 511–535 (1997).

    CAS  PubMed  Google Scholar 

  127. Court, J. et al. Nicotinic receptor abnormalities in Alzheimer's disease. Biol. Psychiatry 49, 175–184 (2001).

    CAS  PubMed  Google Scholar 

  128. Flynn, D. D. & Mash, D. C. Characterization of L-[3H]nicotine binding in human cerebral cortex: comparison between Alzheimer's disease and the normal. J. Neurochem. 47, 1948–1954 (1986).

    CAS  PubMed  Google Scholar 

  129. Whitehouse, P. J. et al. Nicotinic acetylcholine binding sites in Alzheimer's disease. Brain Res. 371, 146–151 (1986).

    CAS  PubMed  Google Scholar 

  130. Aubert, I. et al. Comparative alterations of nicotinic and muscarinic binding sites in Alzheimer's and Parkinson's diseases. J. Neurochem. 58, 529–541 (1992).

    CAS  PubMed  Google Scholar 

  131. Bourin, M., Ripoll, N. & Dailly, E. Nicotinic receptors and Alzheimer's disease. Curr. Med. Res. Opin. 19, 169–177 (2003).

    CAS  PubMed  Google Scholar 

  132. Nordberg, A. Neuroprotection in Alzheimer's disease — new strategies for treatment. Neurotox. Res. 2, 157–165 (2000).

    CAS  PubMed  Google Scholar 

  133. Nordberg, A. et al. Imaging of nicotinic and muscarinic receptors in Alzheimer's disease: effect of tacrine treatment. Dement. Geriatr. Cogn. Disord. 8, 78–84 (1997).

    CAS  PubMed  Google Scholar 

  134. Whitehouse, P. J. & Kalaria, R. N. Nicotinic receptors and neurodegenerative dementing diseases: basic research and clinical implications. Alzheimer Dis. Assoc. Disord. 9, S3–S5 (1995).

    Google Scholar 

  135. Guan, Z. Z., Zhang, X., Ravid, R. & Nordberg, A. Decreased protein levels of nicotinic receptor subunits in the hippocampus and temporal cortex of patients with Alzheimer's disease. J. Neurochem. 74, 237–243 (2000).

    CAS  PubMed  Google Scholar 

  136. Burghaus, L. et al. Quantitative assessment of nicotinic acetylcholine receptor proteins in the cerebral cortex of Alzheimer patients. Brain Res. Mol. Brain Res. 76, 385–388 (2000).

    CAS  PubMed  Google Scholar 

  137. Newhouse, P. A. et al. Intravenous nicotine in Alzheimer's disease: a pilot study. Psychopharmacology (Berl.) 95, 171–175 (1988).

    CAS  Google Scholar 

  138. Newhouse, P. A., Potter, A., Corwin, J. & Lenox, R. Age-related effects of the nicotinic antagonist mecamylamine on cognition and behavior. Neuropsychopharmacology 10, 93–107 (1994).

    CAS  PubMed  Google Scholar 

  139. Newhouse, P. A., Potter, A., Corwin, J. & Lenox, R. Acute nicotinic blockade produces cognitive impairment in normal humans. Psychopharmacology (Berl.) 108, 480–484 (1992).

    CAS  Google Scholar 

  140. Sahakian, B. J. et al. A comparative study of visuospatial memory and learning in Alzheimer-type dementia and Parkinson's disease. Brain 111, 695–718 (1988).

    PubMed  Google Scholar 

  141. Sunderland, T., Tariot, P. N. & Newhouse, P. A. Differential responsivity of mood, behavior, and cognition to cholinergic agents in elderly neuropsychiatric populations. Brain Res. 472, 371–389 (1988).

    CAS  PubMed  Google Scholar 

  142. Rusted, J. M., Newhouse, P. A. & Levin, E. D. Nicotinic treatment for degenerative neuropsychiatric disorders such as Alzheimer's disease and Parkinson's disease. Behav. Brain Res. 113, 121–129 (2000).

    CAS  PubMed  Google Scholar 

  143. Picciotto, M. R. & Zoli, M. Nicotinic receptors in aging and dementia. J. Neurobiol. 53, 641–655 (2002).

    CAS  PubMed  Google Scholar 

  144. Wehner, J. M. et al. Role of neuronal nicotinic receptors in the effects of nicotine and ethanol on contextual fear conditioning. Neuroscience 129, 11–24 (2004).

    CAS  PubMed  Google Scholar 

  145. Keller, J. J., Keller, A. B., Bowers, B. J. & Wehner, J. M. Performance of α7 nicotinic receptor null mutants is impaired in appetitive learning measured in a signaled nose poke task. Behav. Brain Res. 162, 143–152 (2005).

    CAS  PubMed  Google Scholar 

  146. Curzon, P. et al. Antisense knockdown of the rat α7 nicotinic acetylcholine receptor produces spatial memory impairment. Neurosci. Lett. 410, 15–19 (2006).

    CAS  PubMed  Google Scholar 

  147. Fernandes, C., Hoyle, E., Dempster, E., Schalkwyk, L. C. & Collier, D. A. Performance deficit of α7 nicotinic receptor knockout mice in a delayed matching-to-place task suggests a mild impairment of working/episodic-like memory. Genes Brain Behav. 5, 433–440 (2006).

    CAS  PubMed  Google Scholar 

  148. Young, J. W. et al. Impaired attention is central to the cognitive deficits observed in α7 deficient mice. Eur. Neuropsychopharmacol. 17, 145–155 (2007).

    CAS  PubMed  Google Scholar 

  149. Rezvani, A. H. et al. Effect of R3487/MEM3454, a novel nicotinic α7 receptor partial agonist and 5-HT3 antagonist on sustained attention in rats. Prog. Neuropsychopharmacol. Biol. Psychiatry 33, 269–275 (2009).

    CAS  PubMed  Google Scholar 

  150. Kitagawa, H. et al. Safety, pharmacokinetics, and effects on cognitive function of multiple doses of GTS-21 in healthy, male volunteers. Neuropsychopharmacology 28, 542–551 (2003).

    CAS  PubMed  Google Scholar 

  151. Li, X. D. & Buccafusco, J. J. Effect of β-amyloid peptide 1–42 on the cytoprotective action mediated by α7 nicotinic acetylcholine receptors in growth factor-deprived differentiated PC-12 cells. J. Pharmacol. Exp. Ther. 307, 670–675 (2003).

    CAS  PubMed  Google Scholar 

  152. Meyer, E. M. et al. Neuroprotective and memory-related actions of novel α7 nicotinic agents with different mixed agonist/antagonist properties. J. Pharmacol. Exp. Ther. 284, 1026–1032 (1998).

    CAS  PubMed  Google Scholar 

  153. Quik, M. & Kulak, J. M. Nicotine and nicotinic receptors; relevance to Parkinson's disease. Neurotoxicology 23, 581–594 (2002).

    CAS  PubMed  Google Scholar 

  154. Kihara, T. et al. Nicotinic receptor stimulation protects neurons against β-amyloid toxicity. Ann. Neurol. 42, 159–163 (1997).

    CAS  PubMed  Google Scholar 

  155. Martin, S. E., de Fiebre, N. E. & de Fiebre, C. M. The α7 nicotinic acetylcholine receptor-selective antagonist, methyllycaconitine, partially protects against β-amyloid1-42 toxicity in primary neuron-enriched cultures. Brain Res. 1022, 254–256 (2004).

    CAS  PubMed  Google Scholar 

  156. Wang, H. Y., Lee, D. H., Davis, C. B. & Shank, R. P. Amyloid peptide Aβ(1–42) binds selectively and with picomolar affinity to α7 nicotinic acetylcholine receptors. J. Neurochem. 75, 1155–1161 (2000).

    CAS  PubMed  Google Scholar 

  157. Dineley, K. T. et al. β-amyloid activates the mitogen-activated protein kinase cascade via hippocampal α7 nicotinic acetylcholine receptors: in vitro and in vivo mechanisms related to Alzheimer's disease. J. Neurosci. 21, 4125–4133 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Pettit, D. L., Shao, Z. & Yakel, J. L. β-amyloid(1–42) peptide directly modulates nicotinic receptors in the rat hippocampal slice. J. Neurosci. 21, RC120 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  159. Spencer, J. P. et al. Transgenic mice over-expressing human β-amyloid have functional nicotinic α7 receptors. Neuroscience 137, 795–805 (2006).

    CAS  PubMed  Google Scholar 

  160. Small, D. H. et al. The β-amyloid protein of Alzheimer's disease binds to membrane lipids but does not bind to the α7 nicotinic acetylcholine receptor. J. Neurochem. 101, 1527–1538 (2007).

    CAS  PubMed  Google Scholar 

  161. Lamb, P. W., Melton, M. A. & Yakel, J. L. Inhibition of neuronal nicotinic acetylcholine receptor channels expressed in Xenopus oocytes by β-amyloid1–42 peptide. J. Mol. Neurosci. 27, 13–21 (2005).

    CAS  PubMed  Google Scholar 

  162. D'Andrea, M. R. & Nagele, R. G. Targeting the alpha 7 nicotinic acetylcholine receptor to reduce amyloid accumulation in Alzheimer's disease pyramidal neurons. Curr. Pharm. Des. 12, 677–684 (2006).

    CAS  PubMed  Google Scholar 

  163. Hogg, R. C. & Bertrand, D. Partial agonists as therapeutic agents at neuronal nicotinic acetylcholine receptors. Biochem. Pharmacol. 73, 459–468 (2007).

    CAS  PubMed  Google Scholar 

  164. Lipiello, P. M. et al. Nicotinic receptors as targets for therapeutic discovery. Expert Opin. Drug Discov. 2, 1185–1203 (2007).

    Google Scholar 

  165. Curzon, P., Brioni, J. D. & Decker, M. W. Effect of intraventricular injections of dihydro-β-erythroidine (DHβE) on spatial memory in the rat. Brain Res. 714, 185–191 (1996).

    CAS  PubMed  Google Scholar 

  166. Cordero-Erausquin, M., Marubio, L. M., Klink, R. & Changeux, J. P. Nicotinic receptor function: new perspectives from knockout mice. Trends Pharmacol. Sci. 21, 211–217 (2000).

    CAS  PubMed  Google Scholar 

  167. Blondel, A., Sanger, D. J. & Moser, P. C. Characterisation of the effects of nicotine in the five-choice serial reaction time task in rats: antagonist studies. Psychopharmacology (Berl.) 149, 293–305 (2000).

    CAS  Google Scholar 

  168. Granon, S., Faure, P. & Changeux, J. P. Executive and social behaviors under nicotinic receptor regulation. Proc. Natl Acad. Sci. USA 100, 9596–9601 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Hahn, B., Shoaib, M. & Stolerman, I. P. Involvement of the prefrontal cortex but not the dorsal hippocampus in the attention-enhancing effects of nicotine in rats. Psychopharmacology (Berl.) 168, 271–279 (2003).

    CAS  Google Scholar 

  170. Potter, A. et al. Acute effects of the selective cholinergic channel activator (nicotinic agonist) ABT-418 in Alzheimer's disease. Psychopharmacology (Berl.) 142, 334–342 (1999).

    CAS  Google Scholar 

  171. Wilens, T. E. et al. A pilot controlled clinical trial of ABT-418, a cholinergic agonist, in the treatment of adults with attention deficit hyperactivity disorder. Am. J. Psychiatry 156, 1931–1937 (1999).

    CAS  PubMed  Google Scholar 

  172. Wilens, T. E., Verlinden, M. H., Adler, L. A., Wozniak, P. J. & West, S. A. ABT-089, a neuronal nicotinic receptor partial agonist, for the treatment of attention-deficit/hyperactivity disorder in adults: results of a pilot study. Biol. Psychiatry 59, 1065–1070 (2006).

    CAS  PubMed  Google Scholar 

  173. Sharma, T. & Antonova, L. Cognitive function in schizophrenia. Deficits, functional consequences, and future treatment. Psychiatr. Clin. North Am. 26, 25–40 (2003).

    PubMed  Google Scholar 

  174. Adler, L. E., Hoffer, L. J., Griffith, J., Waldo, M. C. & Freedman, R. Normalization by nicotine of deficient auditory sensory gating in the relatives of schizophrenics. Biol. Psychiatry 32, 607–616 (1992).

    CAS  PubMed  Google Scholar 

  175. Freedman, R. et al. Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc. Natl Acad. Sci. USA 94, 587–592 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Freedman, R. & Leonard, S. Genetic linkage to schizophrenia at chromosome 15q14. Am. J. Med. Genet. 105, 655–657 (2001).

    CAS  PubMed  Google Scholar 

  177. Freedman, R., Hall, M., Adler, L. E. & Leonard, S. Evidence in postmortem brain tissue for decreased numbers of hippocampal nicotinic receptors in schizophrenia. Biol. Psychiatry 38, 22–33 (1995).

    CAS  PubMed  Google Scholar 

  178. Stevens, K. E. et al. Genetic correlation of inhibitory gating of hippocampal auditory evoked response and α-bungarotoxin-binding nicotinic cholinergic receptors in inbred mouse strains. Neuropsychopharmacology 15, 152–162 (1996).

    CAS  PubMed  Google Scholar 

  179. Severance, E. G. & Yolken, R. H. Novel α7 nicotinic receptor isoforms and deficient cholinergic transcription in schizophrenia. Genes Brain Behav. 7, 37–45 (2008).

    CAS  PubMed  Google Scholar 

  180. Stevens, K. E. & Wear, K. D. Normalizing effects of nicotine and a novel nicotinic agonist on hippocampal auditory gating in two animal models. Pharmacol. Biochem. Behav. 57, 869–874 (1997).

    CAS  PubMed  Google Scholar 

  181. Simosky, J. K., Stevens, K. E., Adler, L. E. & Freedman, R. Clozapine improves deficient inhibitory auditory processing in DBA/2 mice, via a nicotinic cholinergic mechanism. Psychopharmacology (Berl.) 165, 386–396 (2003).

    CAS  Google Scholar 

  182. Levin, E. D., Ellison, G. D., Salem, C., Jarvik, M. & Gritz, E. Behavioral effects of acute hexamethonium in rats chronically intoxicated with nicotine. Physiol. Behav. 44, 355–359 (1988).

    CAS  PubMed  Google Scholar 

  183. Depatie, L. et al. Nicotine and behavioral markers of risk for schizophrenia: a double-blind, placebo-controlled, cross-over study. Neuropsychopharmacology 27, 1056–1070 (2002).

    CAS  PubMed  Google Scholar 

  184. Rosse, R. B. & Deutsch, S. I. Adjuvant galantamine administration improves negative symptoms in a patient with treatment-refractory schizophrenia. Clin. Neuropharmacol. 25, 272–275 (2002).

    PubMed  Google Scholar 

  185. Koike, K. et al. Tropisetron improves deficits in auditory P50 suppression in schizophrenia. Schizophr. Res. 76, 67–72 (2005).

    PubMed  Google Scholar 

  186. Martin, L. F. & Freedman, R. Schizophrenia and the α7 nicotinic acetylcholine receptor. Int. Rev. Neurobiol. 78, 225–246 (2007).

    CAS  PubMed  Google Scholar 

  187. Olincy, A. et al. Proof-of-concept trial of an α7 nicotinic agonist in schizophrenia. Arch. Gen. Psychiatry 63, 630–638 (2006).

    CAS  PubMed  Google Scholar 

  188. Freedman, R. et al. Initial phase 2 trial of a nicotinic agonist in schizophrenia. Am. J. Psychiatry 165, 1040–1047 (2008).

    PubMed  PubMed Central  Google Scholar 

  189. Leiser, S. C., Bowlby, M. R., Comery, T. A. & Dunlop, J. A cog in cognition: how the α7 nicotinic acetylcholine receptor is geared towards improving cognitive deficits. Pharmacol. Ther. (2009). This article describes the role of α7 nAChR in pro-cognitive effects.

  190. Lieberman, J. A., Javitch, J. A. & Moore, H. Cholinergic agonists as novel treatments for schizophrenia: the promise of rational drug development for psychiatry. Am. J. Psychiatry 165, 931–936 (2008).

    PubMed  Google Scholar 

  191. Fiore, M. C. et al. Integrating smoking cessation treatment into primary care: an effectiveness study. Prev. Med. 38, 412–420 (2004).

    PubMed  Google Scholar 

  192. Di Chiara, G. Role of dopamine in the behavioural actions of nicotine related to addiction. Eur. J. Pharmacol. 393, 295–314 (2000).

    CAS  PubMed  Google Scholar 

  193. Corrigall, W. A. & Coen, K. M. Selective dopamine antagonists reduce nicotine self-administration. Psychopharmacology (Berl.) 104, 171–176 (1991).

    CAS  Google Scholar 

  194. Maskos, U. et al. Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature 436, 103–107 (2005).

    CAS  PubMed  Google Scholar 

  195. Mameli-Engvall, M. et al. Hierarchical control of dopamine neuron-firing patterns by nicotinic receptors. Neuron 50, 911–921 (2006).

    CAS  PubMed  Google Scholar 

  196. Pons, S. et al. Crucial role of α4 and α6 nicotinic acetylcholine receptor subunits from ventral tegmental area in systemic nicotine self-administration. J. Neurosci. 28, 12318–12327 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Balfour, D. J. The neuronal pathways mediating the behavioral and addictive properties of nicotine. Handb. Exp. Pharmacol. 192, 209–233 (2009).

    CAS  Google Scholar 

  198. Picciotto, M. R. et al. Acetylcholine receptors containing the β2 subunit are involved in the reinforcing properties of nicotine. Nature 391, 173–177 (1998).

    CAS  PubMed  Google Scholar 

  199. Watkins, S. S., Epping-Jordan, M. P., Koob, G. F. & Markou, A. Blockade of nicotine self-administration with nicotinic antagonists in rats. Pharmacol. Biochem. Behav. 62, 743–751 (1999).

    CAS  PubMed  Google Scholar 

  200. Rollema, H. et al. Rationale, pharmacology and clinical efficacy of partial agonists of α4β2 nACh receptors for smoking cessation. Trends Pharmacol. Sci. 28, 316–325 (2007).

    CAS  PubMed  Google Scholar 

  201. Besson, M. et al. Long-term effects of chronic nicotine exposure on brain nicotinic receptors. Proc. Natl Acad. Sci. USA 104, 8155–8160 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Lester, H. A. et al. Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery. AAPS J. 11, 167–177 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Exley, R., Clements, M. A., Hartung, H., McIntosh, J. M. & Cragg, S. J. α6-containing nicotinic acetylcholine receptors dominate the nicotine control of dopamine neurotransmission in nucleus accumbens. Neuropsychopharmacology 33, 2158–2166 (2008).

    CAS  PubMed  Google Scholar 

  204. Drenan, R. M. et al. In vivo activation of midbrain dopamine neurons via sensitized, high-affinity α6 nicotinic acetylcholine receptors. Neuron 60, 123–136 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Hung., R. J. et al. A susceptibility locus for lung cancer maps to nicotinic acetylcholine receptor subunit genes on 15q25. Nature 452, 633–637 (2008).

    CAS  PubMed  Google Scholar 

  206. Thorgeirsson, T. E. et al. A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 452, 638–642 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Amos, C. I. et al. Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1. Nature Genet. 40, 616–622 (2008).

    CAS  PubMed  Google Scholar 

  208. Salas, R., Pieri, F. & De Biasi, M. Decreased signs of nicotine withdrawal in mice null for the β4 nicotinic acetylcholine receptor subunit. J. Neurosci. 24, 10035–10039 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Janowsky, D. S., el-Yousef, M. K., Davis, J. M. & Sakerke, H. J. A cholinergic-adrenergic hypothesis of mania and depression. Lancet 2, 632–635 (1972).

    CAS  PubMed  Google Scholar 

  210. Shytle, R. D. et al. Nicotinic acetylcholine receptors as targets for antidepressants. Mol. Psychiatry 7, 525–535 (2002).

    CAS  PubMed  Google Scholar 

  211. Garcia-Colunga, J., Awad, J. N. & Miledi, R. Blockage of muscle and neuronal nicotinic acetylcholine receptors by fluoxetine (Prozac). Proc. Natl Acad. Sci. USA 94, 2041–2044 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Hennings, E. C., Kiss, J. P. & Vizi, E. S. Nicotinic acetylcholine receptor antagonist effect of fluoxetine in rat hippocampal slices. Brain Res. 759, 292–294 (1997).

    CAS  PubMed  Google Scholar 

  213. Maggi, L., Palma, E., Miledi, R. & Eusebi, F. Effects of fluoxetine on wild and mutant neuronal α7 nicotinic receptors. Mol. Psychiatry 3, 350–355 (1998).

    CAS  PubMed  Google Scholar 

  214. Fryer, J. D. & Lukas, R. J. Antidepressants noncompetitively inhibit nicotinic acetylcholine receptor function. J. Neurochem. 72, 1117–1124 (1999).

    CAS  PubMed  Google Scholar 

  215. Hennings, E. C., Kiss, J. P., De Oliveira, K., Toth, P. T. & Vizi, E. S. Nicotinic acetylcholine receptor antagonistic activity of monoamine uptake blockers in rat hippocampal slices. J. Neurochem. 73, 1043–1050 (1999).

    CAS  PubMed  Google Scholar 

  216. Kiss, J. P., Hennings, E. C., De Oliveira, K., Toth, P. T. & Vizi, E. S. Nicotinic acetylcholine receptor antagonistic activity of the selective dopamine uptake blocker GBR-12909 in rat hippocampal slices. J. Physiol. 526 (2000).

  217. Charles, H. C. et al. Brain choline in depression: in vivo detection of potential pharmacodynamic effects of antidepressant therapy using hydrogen localized spectroscopy. Prog. Neuropsychopharmacol. Biol. Psychiatry 18, 1121–1127 (1994).

    CAS  PubMed  Google Scholar 

  218. Steingard, R. J. et al. Increased orbitofrontal cortex levels of choline in depressed adolescents as detected by in vivo proton magnetic resonance spectroscopy. Biol. Psychiatry 48, 1053–1061 (2000).

    CAS  PubMed  Google Scholar 

  219. Popik, P., Kozela, E. & Krawczyk, M. Nicotine and nicotinic receptor antagonists potentiate the antidepressant-like effects of imipramine and citalopram. Br. J. Pharmacol. 139, 1196–1202 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  220. Rabenstein, R. L., Caldarone, B. J. & Picciotto, M. R. The nicotinic antagonist mecamylamine has antidepressant-like effects in wild-type but not β2- or α7-nicotinic acetylcholine receptor subunit knockout mice. Psychopharmacology (Berl.) 189, 395–401 (2006).

    CAS  Google Scholar 

  221. Mineur, Y. S., Somenzi, O. & Picciotto, M. R. Cytisine, a partial agonist of high-affinity nicotinic acetylcholine receptors, has antidepressant-like properties in male C57BL/56J mice. Neuropharmacology 52, 1256–1262 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. Andreasen, J. T., Olsen, G. M., Wiborg, O. & Redrobe, J. P. Antidepressant-like effects of nicotinic acetylcholine receptor antagonists, but not agonists, in the mouse forced swim and mouse tail suspension tests. J. Psychopharmacol. (doi:10.1177/0269881108091587) (2008).

    PubMed  Google Scholar 

  223. Shytle, R. D., Silver, A. A. & Sanberg, P. R. Comorbid bipolar disorder in Tourette's syndrome responds to the nicotinic receptor antagonist mecamylamine (Inversine). Biol. Psychiatry 48, 1028–1031 (2000).

    CAS  PubMed  Google Scholar 

  224. Shytle, R. D., Silver, A. A., Sheehan, K. H., Sheehan, D. V. & Sanberg, P. R. Neuronal nicotinic receptor inhibition for treating mood disorders: preliminary controlled evidence with mecamylamine. Depress. Anxiety 16, 89–92 (2002).

    PubMed  Google Scholar 

  225. McClernon, F. J., Hiott, F. B., Westman, E. C., Rose, J. E. & Levin, E. D. Transdermal nicotine attenuates depression symptoms in nonsmokers: a double-blind, placebo-controlled trial. Psychopharmacology (Berl.) 189, 125–133 (2006).

    CAS  Google Scholar 

  226. George, T. P., Sacco, K. A., Vessicchio, J. C., Weinberger, A. H. & Shytle, R. D. Nicotinic antagonist augmentation of selective serotonin reuptake inhibitor-refractory major depressive disorder: a preliminary study. J. Clin. Psychopharmacol. 28, 340–344 (2008).

    PubMed  Google Scholar 

  227. Fedorov, N., Moore, L., Gatto, G., Jordan, K. & Bencherif, M. Differential effects of TC-5214 [S-(+)-mecamylamine] and TC-5213 [R-(-)-mecamylamine] at low and high sensitivity human α4β2 nicotinic receptors and in animal models of depression and anxiety. The Society for Neuroscience, abstr. 39.2 (2007).

  228. Marubio, L. M. et al. Reduced antinociception in mice lacking neuronal nicotinic receptor subunits. Nature 398, 805–810 (1999).

    CAS  PubMed  Google Scholar 

  229. Damaj, M. I. Nicotinic regulation of calcium/calmodulin-dependent protein kinase II activation in the spinal cord. J. Pharmacol. Exp. Ther. 320, 244–249 (2007).

    CAS  PubMed  Google Scholar 

  230. Cordero-Erausquin, M. & Changeux, J. P. Tonic nicotinic modulation of serotoninergic transmission in the spinal cord. Proc. Natl Acad. Sci. USA 98, 2803–2807 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. Donnelly-Roberts, D. L. et al. ABT-594 [(R)-5-(2-azetidinylmethoxy)-2-chloropyridine]: a novel, orally effective analgesic acting via neuronal nicotinic acetylcholine receptors: I. In vitro characterization. J. Pharmacol. Exp. Ther. 285, 777–786 (1998).

    CAS  PubMed  Google Scholar 

  232. Bannon, A. W. et al. Broad-spectrum, non-opioid analgesic activity by selective modulation of neuronal nicotinic acetylcholine receptors. Science 279, 77–81 (1998).

    CAS  PubMed  Google Scholar 

  233. Decker, M. W. et al. The role of neuronal nicotinic acetylcholine receptors in antinociception: effects of ABT-594. J. Physiol. Paris 92, 221–224 (1998).

    CAS  PubMed  Google Scholar 

  234. Bitner, R. S. et al. Role of the nucleus raphe magnus in antinociception produced by ABT-594: immediate early gene responses possibly linked to neuronal nicotinic acetylcholine receptors on serotonergic neurons. J. Neurosci. 18, 5426–5432 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  235. Decker, M. W. & Meyer, M. D. Therapeutic potential of neuronal nicotinic acetylcholine receptor agonists as novel analgesics. Biochem. Pharmacol. 58, 917–923 (1999).

    CAS  PubMed  Google Scholar 

  236. Ji, J. et al. A-366833: a novel nicotinonitrile-substituted 3,6-diazabicyclo[3.2.0]-heptane α4β2 nicotinic acetylcholine receptor selective agonist: synthesis, analgesic efficacy and tolerability profile in animal models. Biochem. Pharmacol. 74, 1253–1262 (2007).

    CAS  PubMed  Google Scholar 

  237. Clark, R. J., Fischer, H., Nevin, S. T., Adams, D. J. & Craik, D. J. The synthesis, structural characterization, and receptor specificity of the a-conotoxin Vc1.1. J. Biol. Chem. 281, 23254–23263 (2006).

    CAS  PubMed  Google Scholar 

  238. Ellison, M. et al. α-RgIA: a novel conotoxin that specifically and potently blocks the α9α10 nAChR. Biochemistry 45, 1511–1517 (2006).

    CAS  PubMed  Google Scholar 

  239. Peng, C. et al. Discovery of a novel class of conotoxin from Conus litteratus, lt14a, with a unique cysteine pattern. Peptides 27, 2174–2181 (2006).

    CAS  PubMed  Google Scholar 

  240. Clark, R. J. et al. The three-dimensional structure of the analgesic α-conotoxin, RgIA. FEBS Lett. 582, 597–602 (2008).

    CAS  PubMed  Google Scholar 

  241. Ellison, M. et al. α-RgIA, a novel conotoxin that blocks the α9α10 nAChR: structure and identification of key receptor-binding residues. J. Mol. Biol. 377, 1216–1227 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  242. Satkunanathan, N. et al. α-conotoxin Vc1.1 alleviates neuropathic pain and accelerates functional recovery of injured neurones. Brain Res. 1059, 149–158 (2005).

    CAS  PubMed  Google Scholar 

  243. Vincler, M. et al. Molecular mechanism for analgesia involving specific antagonism of α9α10 nicotinic acetylcholine receptors. Proc. Natl Acad. Sci. USA 103, 17880–17884 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  244. Nevin, S. T. et al. Are α9α10 nicotinic acetylcholine receptors a pain target for α-conotoxins? Mol. Pharmacol. 72, 1406–1410 (2007).

    CAS  PubMed  Google Scholar 

  245. Callaghan, B. et al. Analgesic α-conotoxins Vc1.1 and Rg1A inhibit N-type calcium channels in rat sensory neurons via GABAB receptor activation. J. Neurosci. 28, 10943–10951 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  246. Livingstone, P. D. et al. α7 and non-α7 nicotinic acetylcholine receptors modulate dopamine release in vitro and in vivo in the rat prefrontal cortex. Eur. J. Neurosci. 29, 539–550 (2009).

    PubMed  Google Scholar 

  247. Wonnacott, S. Gates and filters: unveiling the physiological roles of nicotine receptors in dopaminergic transmission. Br. J. Pharmacol. 153, S2–S4 (2008). This article analyses the role of nAChRs in dopaminergic signalling.

    CAS  PubMed  PubMed Central  Google Scholar 

  248. Schapira, A. H. V. et al. Novel pharmacological targets for the treatment of Parkinson's disease. Nature Rev. Drug Discov. 5 845–854 (2006).

    CAS  Google Scholar 

  249. Janhunen, S. & Ahtee, L. Differential nicotinic regulation of the nigrostriatal and mesolimbic dopaminergic pathways: implications for drug development. Neurosci. Biobehav. Rev. 31, 287–314 (2007).

    CAS  PubMed  Google Scholar 

  250. Granon, S. & Changeux, J. P. Attention-deficit/hyperactivity disorder: a plausible mouse model? Acta Paediatr. 95, 645–649 (2006).

    PubMed  Google Scholar 

  251. Sullivan, J. P. et al. ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine]: I. A potent and selective cholinergic channel modulator with neuroprotective properties. J. Pharmacol. Exp. Ther. 283, 235–246 (1997).

    CAS  PubMed  Google Scholar 

  252. Zheng, G., Dwoskin, L. P., Deaciuc, A. G., Norrholm, S. D. & Crooks, P. A. Defunctionalized lobeline analogues: structure-activity of novel ligands for the vesicular monoamine transporter. J. Med. Chem. 48, 5551–5560 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  253. Cartaud, J., Benedetti, E. L., Cohen, J. B., Meunier, J. C. & Changeux, J. P. Presence of a lattice structure in membrane fragments rich in nicotinic receptor protein from the electric organ of Torpedo marmorata. FEBS Lett. 33, 109–113 (1973).

    CAS  PubMed  Google Scholar 

  254. Unwin, N. Refined structure of the nicotinic acetylcholine receptor at 4Å resolution. J. Mol. Biol. 346, 967–989 (2005).

    CAS  PubMed  Google Scholar 

  255. Miyazawa, A., Fujiyoshi, Y. & Unwin, N. Structure and gating mechanism of the acetylcholine receptor pore. Nature 423, 949–955 (2003). This paper provided the first 4-Å resolution structure of the transmembrane domain of nAChRs.

    CAS  PubMed  Google Scholar 

  256. Blanton, M. P. & Cohen, J. B. Identifying the lipid-protein interface of the Torpedo nicotinic acetylcholine receptor: secondary structure implications. Biochemistry 33, 2859–2872 (1994).

    CAS  PubMed  Google Scholar 

  257. Tasneem, A., Iyer, L. M., Jakobsson, E. & Aravind, L. Identification of the prokaryotic ligand-gated ion channels and their implications for the mechanisms and origins of animal Cys-loop ion channels. Genome Biol. 6, R4 (2005).

    PubMed  Google Scholar 

  258. Dellisanti, C. D., Yao, Y., Stroud, J. C., Wang, Z. Z. & Chen, L. Crystal structure of the extracellular domain of nAChR α1 bound to α-bungarotoxin at 1.94 Å resolution. Nature Neurosci. 10, 953–962 (2007).

    CAS  PubMed  Google Scholar 

  259. Jansen, M., Bali, M. & Akabas, M. H. Modular design of Cys-loop ligand-gated ion channels: functional 5-HT3 and GABA ρ1 receptors lacking the large cytoplasmic M3M4 loop. J. Gen. Physiol. 131, 137–146 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  260. Hucho, F., Oberthur, W. & Lottspeich, F. The ion channel of the nicotinic acetylcholine receptor is formed by the homologous helices M II of the receptor subunits. FEBS Lett. 205, 137–142 (1986).

    CAS  PubMed  Google Scholar 

  261. Imoto, K. et al. Rings of negatively charged amino acids determine the acetylcholine receptor channel conductance. Nature 335, 645–648 (1988).

    CAS  PubMed  Google Scholar 

  262. Galzi, J. L. et al. Mutations in the channel domain of a neuronal nicotinic receptor convert ion selectivity from cationic to anionic. Nature 359, 500–505 (1992).

    CAS  PubMed  Google Scholar 

  263. Corringer, P. J. et al. Molecular basis of the charge selectivity of nicotinic acetylcholine receptor and related ligand-gated ion channels. Novartis Found. Symp. 225, 215–224; discussion 224–30 (1999).

    CAS  PubMed  Google Scholar 

  264. Wotring, V. E. & Weiss, D. S. Charge scan reveals an extended region at the intracellular end of the GABA receptor pore that can influence ion selectivity. J. Gen. Physiol. 131, 87–97 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  265. Keramidas, A., Moorhouse, A. J., Schofield, P. R. & Barry, P. H. Ligand-gated ion channels: mechanisms underlying ion selectivity. Prog. Biophys. Mol. Biol. 86, 161–204 (2004).

    CAS  PubMed  Google Scholar 

  266. Sunesen, M. et al. Mechanism of Cl selection by a glutamate-gated chloride (GluCl) receptor revealed through mutations in the selectivity filter. J. Biol. Chem. 281, 14875–14881 (2006).

    CAS  PubMed  Google Scholar 

  267. Gunthorpe, M. J. & Lummis, S. C. Conversion of the ion selectivity of the 5-HT3a receptor from cationic to anionic reveals a conserved feature of the ligand-gated ion channel superfamily. J. Biol. Chem. 276, 10977–10983 (2001).

    CAS  PubMed  Google Scholar 

  268. Corringer, P. J. et al. Mutational analysis of the charge selectivity filter of the α7 nicotinic acetylcholine receptor. Neuron 22, 831–843 (1999).

    CAS  PubMed  Google Scholar 

  269. Bertrand, D., Galzi, J. L., Devillers-Thiery, A., Bertrand, S. & Changeux, J. P. Mutations at two distinct sites within the channel domain M2 alter calcium permeability of neuronal α7 nicotinic receptor. Proc. Natl Acad. Sci. USA 90, 6971–6975 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  270. Changeux, J. P. Allosteric interactions interpreted in terms of quaternary structure. Brookhaven Symp. Biol. 17, 232–249 (1964).

    CAS  PubMed  Google Scholar 

  271. Cui, Q. & Karplus, M. Allostery and cooperativity revisited. Protein Sci. 17, 1295–1307 (2008). A recent review of the relevance of the concept of allostery in molecular dynamics studies.

    CAS  PubMed  PubMed Central  Google Scholar 

  272. Adair, G. S. The hemoglobin system. VI. The oxygen dissociation curve of hemoglobin. J. Biol. Chem. 63, 529–545 (1925).

    CAS  Google Scholar 

  273. Koshland, D. E. Jr. Correlation of structure and function in enzyme action. Science 142, 1533–1541 (1963).

    CAS  PubMed  Google Scholar 

  274. Colquhoun, D. & Sakmann, B. From muscle endplate to brain synapses: a short history of synapses and agonist-activated ion channels. Neuron 20, 381–387 (1998).

    CAS  PubMed  Google Scholar 

  275. Monod, J., Wyman, J. & Changeux, J. P. On the nature of allosteric transitions: a plausible model. J. Mol. Biol. 12, 88–118 (1965).

    CAS  PubMed  Google Scholar 

  276. Katz, B. & Thesleff, S. A study of the desensitization produced by acetylcholine at the motor end-plate. J. Physiol. 138, 63–80 (1957).

    CAS  PubMed  PubMed Central  Google Scholar 

  277. Bouzat, C., Bartos, M., Corradi, J. & Sine, S. M. The interface between extracellular and transmembrane domains of homomeric Cys-loop receptors governs open-channel lifetime and rate of desensitization. J. Neurosci. 28, 7808–7819 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  278. White, B. H. & Cohen, J. B. Agonist-induced changes in the structure of the acetylcholine receptor M2 regions revealed by photoincorporation of an uncharged nicotinic noncompetitive antagonist. J. Biol. Chem. 267, 15770–15783 (1992).

    CAS  PubMed  Google Scholar 

  279. Le Novere, N., Corringer, P. J. & Changeux, J. P. The diversity of subunit composition in nAChRs: evolutionary origins, physiologic and pharmacologic consequences. J. Neurobiol. 53, 447–456 (2002).

    CAS  PubMed  Google Scholar 

  280. Gotti, C., Zoli, M. & Clementi, F. Brain nicotinic acetylcholine receptors: native subtypes and their relevance. Trends Pharmacol. Sci. 27, 482–491 (2006).

    CAS  PubMed  Google Scholar 

  281. Biton, B. et al. SSR180711, a novel selective α7 nicotinic receptor partial agonist: (1) binding and functional profile. Neuropsychopharmacology 32, 1–16 (2007).

    CAS  PubMed  Google Scholar 

  282. Sydserff, S. et al. Selective α7 nicotinic receptor activation by AZD0328 enhances cortical dopamine release and improves learning and attentional processes. Biochem. Pharmacol. 22 Apr 2009 (doi:10.1016/j.bcp.2009.07.005).

    CAS  PubMed  Google Scholar 

  283. Lopez-Hernandez, G. et al. Partial agonist and neuromodulatory activity of S 24795 for α7 nAChR responses of hippocampal interneurons. Neuropharmacology 53, 134–144 (2007).

    CAS  PubMed  Google Scholar 

  284. Hauser, T. A. et al. TC-5619: an α7 neuronal nicotinic receptor-selective agonist that demonstrates efficacy in animal models of the positive and negative symptoms and cognitive dysfunction of schizophrenia. Biochem. Pharmacol. 24 Mar 2009 (doi:10.1016/j.bcp.2009.05.030).

    CAS  PubMed  PubMed Central  Google Scholar 

  285. Cohen, C. et al. SSR591813, a novel selective and partial α4β2 nicotinic receptor agonist with potential as an aid to smoking cessation. J. Pharmacol. Exp. Ther. 306, 407–420 (2003).

    CAS  PubMed  Google Scholar 

  286. Dunbar, G. et al. Pharmacokinetics and safety profile of ispronicline (TC-1734), a new brain nicotinic receptor partial agonist, in young healthy male volunteers. J. Clin. Pharmacol. 46, 715–726 (2006).

    CAS  PubMed  Google Scholar 

  287. Lippiello, P. M. et al. TC-5214 (S-(+)-mecamylamine): a neuronal nicotinic receptor modulator with antidepressant activity. CNS Neurosci. Ther. 14, 266–277 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  288. Dziewczapolski, G., Glogowski, C. M., Masliah, E. & Heinemann, S. F. Deletion of the α7 nicotinic acetylcholine receptor gene improves cognitive deficits and synaptic pathology in a mouse model of Alzheimer's disease. J. Neurosci. 29, 8805–8815 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  289. Jackson, K. J., Martin, B. R., Changeux, J. P. & Damaj, M. I. Differential role of nicotinic acetylcholine receptor subunits in physical and affective nicotine withdrawal signs. J. Pharmacol. Exp. Ther. 325, 302–312 (2008).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Ethics declarations

Competing interests

A.T. receives a grant from Servier laboratories. D.G. and P.l. are employees of Servier laboratories.

Related links

Related links

DATABASES

OMIM

Alzheimer's disease

attention deficit hyperactivity disorder

depression

schizophrenia

FURTHER INFORMATION

Targacept provides update on TC-6499 and pain program in GlaxoSmithKline Alliance

Glossary

Oligomer

A particular category of protein that results from the assembly of identical or homologous subunits and possesses axes of symmetry.

Allosteric transition

The global conformational change that brings together the multiple topographically distinct sites carried by a regulatory protein.

Orthosteric binding site

The main biologically active site of a receptor, to which the cognate ligand binds.

Induced fit

A conformational change in a receptor, proposed by Koshland, that is induced after a ligand is bound, with the consequence that the receptor conformation locally adapts to, and indefinitely varies with, the structure of the ligand.

Quaternary twist

A global rotational motion of the receptor protein, resulting from a tilt of each subunit, that leads to the opening of the ion channel and a structural reorganization of the acetylcholine-binding site.

Monod–Wyman–Changeux model

A molecular mechanism that was initially proposed in 1965 to account for the allosteric interactions mediated by a large body of regulatory enzymes. It posits that the protein oligomer spontaneously undergoes reversible transitions between at least two discrete and symmetrical conformational states, even in the absence of agonist, and that ligands selectively stabilize any one of these states through a process of conformational selection.

P50 auditory gating

The ability of a healthy organism to suppress the evoked response to an auditory stimulus that occurs 50 ms after a first stimulation.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Taly, A., Corringer, PJ., Guedin, D. et al. Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system. Nat Rev Drug Discov 8, 733–750 (2009). https://doi.org/10.1038/nrd2927

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd2927

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing