Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system (original) (raw)

• Changeux, J. P. & Edelstein, S. J. Allosteric mechanisms of signal transduction. Science 308, 1424–1428 (2005).
  CAS PubMed Google Scholar
• 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
• 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
• Sine, S. M. & Engel, A. G. Recent advances in Cys-loop receptor structure and function. Nature 440, 448–455 (2006).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• Sallette, J. et al. Nicotine upregulates its own receptors through enhanced intracellular maturation. Neuron 46, 595–607 (2005).
  CAS PubMed Google Scholar
• 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
• 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
• Romanelli, M. N. et al. Central nicotinic receptors: structure, function, ligands, and therapeutic potential. ChemMedChem 2, 746–767 (2007).
  CAS PubMed Google Scholar
• Changeux, J. P. & Taly, A. Nicotinic receptors, allosteric proteins and medicine. Trends Mol. Med. 14, 93–102 (2008).
  CAS PubMed Google Scholar
• Gotti, C. et al. Heterogeneity and complexity of native brain nicotinic receptors. Biochem. Pharmacol. 74, 1102–1111 (2007).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• Grutter, T. & Changeux, J. P. Nicotinic receptors in wonderland. Trends Biochem. Sci. 26, 459–463 (2001).
  CAS PubMed Google Scholar
• 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
• Sine, S. M. The nicotinic receptor ligand binding domain. J. Neurobiol. 53, 431–446 (2002).
  CAS PubMed Google Scholar
• 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
• Kalamida, D. et al. Muscle and neuronal nicotinic acetylcholine receptors. Structure, function and pathogenicity. FEBS J. 274, 3799–3845 (2007).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Dutertre, S. & Lewis, R. J. Toxin insights into nicotinic acetylcholine receptors. Biochem. Pharmacol. 72, 661–670 (2006).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• Bertrand, D. & Gopalakrishnan, M. Allosteric modulation of nicotinic acetylcholine receptors. Biochem. Pharmacol. 74, 1155–1163 (2007).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• Sigel, E. Mapping of the benzodiazepine recognition site on GABAA receptors. Curr. Top. Med. Chem. 2, 833–839 (2002).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Taly, A. Opened by a twist: a gating mechanism for the nicotinic acetylcholine receptor. Eur. Biophys. J. 36, 911–918 (2007).
  PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Schuller, H. M. Is cancer triggered by altered signalling of nicotinic acetylcholine receptors? Nature Rev. Cancer 9, 195–205 (2009).
  CAS Google Scholar
• 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
• 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
• 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
• 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
• Kasa, P., Rakonczay, Z. & Gulya, K. The cholinergic system in Alzheimer's disease. Prog. Neurobiol. 52, 511–535 (1997).
  CAS PubMed Google Scholar
• Court, J. et al. Nicotinic receptor abnormalities in Alzheimer's disease. Biol. Psychiatry 49, 175–184 (2001).
  CAS PubMed Google Scholar
• 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
• Whitehouse, P. J. et al. Nicotinic acetylcholine binding sites in Alzheimer's disease. Brain Res. 371, 146–151 (1986).
  CAS PubMed Google Scholar
• 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
• Bourin, M., Ripoll, N. & Dailly, E. Nicotinic receptors and Alzheimer's disease. Curr. Med. Res. Opin. 19, 169–177 (2003).
  CAS PubMed Google Scholar
• Nordberg, A. Neuroprotection in Alzheimer's disease — new strategies for treatment. Neurotox. Res. 2, 157–165 (2000).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• Newhouse, P. A. et al. Intravenous nicotine in Alzheimer's disease: a pilot study. Psychopharmacology (Berl.) 95, 171–175 (1988).
  CAS Google Scholar
• 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
• 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
• 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
• 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
• 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
• Picciotto, M. R. & Zoli, M. Nicotinic receptors in aging and dementia. J. Neurobiol. 53, 641–655 (2002).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Quik, M. & Kulak, J. M. Nicotine and nicotinic receptors; relevance to Parkinson's disease. Neurotoxicology 23, 581–594 (2002).
  CAS PubMed Google Scholar
• Kihara, T. et al. Nicotinic receptor stimulation protects neurons against β-amyloid toxicity. Ann. Neurol. 42, 159–163 (1997).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Lipiello, P. M. et al. Nicotinic receptors as targets for therapeutic discovery. Expert Opin. Drug Discov. 2, 1185–1203 (2007).
  Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Freedman, R. & Leonard, S. Genetic linkage to schizophrenia at chromosome 15q14. Am. J. Med. Genet. 105, 655–657 (2001).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Koike, K. et al. Tropisetron improves deficits in auditory P50 suppression in schizophrenia. Schizophr. Res. 76, 67–72 (2005).
  PubMed Google Scholar
• Martin, L. F. & Freedman, R. Schizophrenia and the α7 nicotinic acetylcholine receptor. Int. Rev. Neurobiol. 78, 225–246 (2007).
  CAS PubMed Google Scholar
• 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
• 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
• 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.
• 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
• Fiore, M. C. et al. Integrating smoking cessation treatment into primary care: an effectiveness study. Prev. Med. 38, 412–420 (2004).
  PubMed Google Scholar
• 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
• Corrigall, W. A. & Coen, K. M. Selective dopamine antagonists reduce nicotine self-administration. Psychopharmacology (Berl.) 104, 171–176 (1991).
  CAS Google Scholar
• Maskos, U. et al. Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature 436, 103–107 (2005).
  CAS PubMed Google Scholar
• Mameli-Engvall, M. et al. Hierarchical control of dopamine neuron-firing patterns by nicotinic receptors. Neuron 50, 911–921 (2006).
  CAS PubMed Google Scholar
• 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
• Balfour, D. J. The neuronal pathways mediating the behavioral and addictive properties of nicotine. Handb. Exp. Pharmacol. 192, 209–233 (2009).
  CAS Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Shytle, R. D. et al. Nicotinic acetylcholine receptors as targets for antidepressants. Mol. Psychiatry 7, 525–535 (2002).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• Fryer, J. D. & Lukas, R. J. Antidepressants noncompetitively inhibit nicotinic acetylcholine receptor function. J. Neurochem. 72, 1117–1124 (1999).
  CAS PubMed Google Scholar
• 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
• 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).
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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).
• Marubio, L. M. et al. Reduced antinociception in mice lacking neuronal nicotinic receptor subunits. Nature 398, 805–810 (1999).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Granon, S. & Changeux, J. P. Attention-deficit/hyperactivity disorder: a plausible mouse model? Acta Paediatr. 95, 645–649 (2006).
  PubMed Google Scholar
• 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
• 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
• 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
• Unwin, N. Refined structure of the nicotinic acetylcholine receptor at 4Å resolution. J. Mol. Biol. 346, 967–989 (2005).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• Changeux, J. P. Allosteric interactions interpreted in terms of quaternary structure. Brookhaven Symp. Biol. 17, 232–249 (1964).
  CAS PubMed Google Scholar
• 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
• Adair, G. S. The hemoglobin system. VI. The oxygen dissociation curve of hemoglobin. J. Biol. Chem. 63, 529–545 (1925).
  CAS Google Scholar
• Koshland, D. E. Jr. Correlation of structure and function in enzyme action. Science 142, 1533–1541 (1963).
  CAS PubMed Google Scholar
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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