Nicotinic Acetylcholine Receptors

Abstract

Nicotinic acetylcholine receptors (AChRs) bind the neurotransmitter acetylcholine, triggering the opening of a cation channel. AChRs are part of a gene superfamily of transmitter gated ion channels that include receptors for glycine and γ‐amino butyric acid which have anion channels. Muscarinic AChRs are part of a gene superfamily of metabotropic G protein‐linked receptors. AChRs are formed from five homologous subunits arranged like barrel staves to form the channel. Subtypes of AChRs are defined by their subunit composition. Studies of AChR subunits in knockout and transgenic mice reveal much about the normal physiological roles of AChR subtypes and their roles in disease. AChRs are the targets of nicotine in addiction to tobacco, of auto‐antibodies and disease‐causing mutations. They are also the targets of drug development for treatment of addiction and diseases of mood, cognition and neurodegeneration.

Key Concepts:

  • Nicotinic AChRs are the archetype for a superfamily of receptors which includes receptors for GABA and glycine.

  • AChR are formed by five homologous subunits organised around a central cation channel.

  • AChR subtypes are defined by their subunit composition.

  • AChRs serve many roles in excitatory intercellular signalling: as pre‐, post‐ and extra‐synaptic neurotransmitter receptors and as autocrine AChRs in nonneuronal tissues.

  • Nicotine acting on AChRs causes addiction to tobacco.

  • AChRs are involved in several diseases and are the targets of drug development for treatment of addiction, alcoholism, depression, schizophrenia, Alzheimer and Parkinson diseases and others.

  • The effects of nicotine and agonist drugs are complex because they can act on many AChR subtypes causing activation, desensitisation and upregulation.

  • Antibody‐mediated autoimmune responses to α1* AChRs cause myasthenia gravis and to α3* AChRs cause autonomic neuropathy. These diseases are models for the pathological mechanisms of autoantibodies to other receptors.

  • Mutations in α1* AChRs cause congenital myasthenic syndromes, and mutations in α4β2* AChRs cause autosomal dominant nocturnal frontal lobe epilepsy.

Keywords: tobacco; myasthenia gravis; neuromuscular transmission; electric organs; nicotine

Figure 1.

Crystal structures of muscle type AChRs and some related proteins. (a) Torpedo electric organ α1*AChRs, (b) mollusc glial ACh binding protein and (c) bacterial AChR –like protein ELIC. (a) Reproduced from Unwin , with permission from Elsevier. (b) Reproduced from Brejc et al., with permission from Nature Publishing Group. (c) Reproduced from Hilf and Dutzler , with permission from Nature Publishing Group.

Figure 2.

Conformation changes associated with ligand binding illustrated by changes in the crystal structure of the ACh binding protein. The C‐loop opens to provide access to the ACh binding sites in the resting state and is propped open by binding of large antagonists. The C‐loop closes over the ACh binding sites when small agonists are bound. Reproduced from Hansen et al., with permission from Nature Publishing Group.

Figure 3.

Subunit compositions and arrangements of important AChR subtypes.

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References

Brejc K, van Dijk WJ, Klaassen RV et al. (2001) Crystal structure of an ACh‐binding protein reveals the ligand‐binding domain of nicotinic receptors. Nature 411: 269–276.

Brown RW, Collins AC, Lindstrom JM and Whiteaker P (2007) Nicotinic α5 subunit deletion locally reduces high‐affinity agonist activation without altering nicotinic receptor numbers. Journal of Neurochemistry 103: 204–215.

Caldarone BJ, Harrist A, Cleary MA et al. (2004) High‐affinity nicotinic acetylcholine receptors are required for antidepressant effects of amitriptyline on behavior and hippocampal cell proliferation. Biological Psychiatry 56: 657–664.

Corringer PJ, Le Novere N and Changeux JP (2000) Nicotinic receptors at the amino acid level. Annual Review of Pharmacology and Toxicology 40: 431–458.

Cui C, Booker TK, Allen RS et al. (2003) The β3 nicotinic receptor subunit: a component of α‐conotoxin MII‐binding nicotinic acetylcholine receptors that modulate dopamine release and related behaviors. Journal of Neuroscience 23: 11045–11053.

Drenan RM, Grady SR, Whiteaker P et al. (2008) In vivo activation of midbrain dopamine neurons via sensitized, high‐affinity α6 nicotinic acetylcholine receptors. Neuron 60: 123–136.

Dziewczapolski G, Glogowski CM, Masliah E and Heinemann SF (2009) Deletion of the α7 nicotinic acetylcholine receptor gene improves cognitive deficits and synaptic pathology in a mouse model of Alzheimer's disease. Journal of Neuroscience 29: 8805–8815.

Elgoyhen AB, Katz E and Fuchs PA (2009) The nicotinic receptor of cochlear hair cells: a possible pharmacotherapeutic target? Biochemical Pharmacology 78: 712–719.

Gotti C, Moretti M, Meinerz NM et al. (2008) Partial deletion of the nicotinic cholinergic receptor α4 or β2 subunit genes changes the acetylcholine sensitivity of receptor‐mediated 86Rb+ efflux in cortex and thalamus and alters relative expression of α4 and β2 subunits. Molecular Pharmacology 73: 1796–1807.

Grando SA (2008) Basic and clinical aspects of non‐neuronal acetylcholine: biological and clinical significance of non‐canonical ligands of epithelial nicotinic acetylcholine receptors. Journal of Pharmacological Sciences 106: 174–179.

Hansen SB, Sulzenbacher G, Huxford T et al. (2005) Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and confirmations. EMBO Journal 24: 3635–3646.

Hilf RJC and Dutzler R (2008) Structure of a potentially open state of a proton‐activated pentameric ligand‐gated ion channel. Nature 457: 115–118.

Hoda JC, Gu W, Friedli M et al. (2008) Human nocturnal frontal lobe epilepsy: pharmocogenomic profiles of pathogenic nicotinic acetylcholine receptor beta‐subunit mutations outside the ion channel pore. Molecular Pharmacology 74: 379–391.

Huang LZ, Parameswaran N, Bordia T, Michael McIntosh J and Quik M (2009) Nicotine is neuroprotective when administered before but not after nigrostriatal damage in rats and monkeys. Journal of Neurochemistry 109: 826–837.

Kedmi M, Beaudet AL and Orr‐Urtreger A (2004) Mice lacking neuronal nicotinic acetylcholine receptor β4‐subunit and mice lacking both α5‐ and β4‐subunits are highly resistant to nicotine‐induced seizures. Physiological Genomics 17: 221–229.

Klaassen A, Glykys J, Maguire J et al. (2006) Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy. Proceedings of the National Academy of Sciences of the USA 103: 19152–19157.

Kuryatov A, Luo J, Cooper J and Lindstrom J (2005) Nicotine acts as a pharmacological chaperone to up‐regulate human α4β2 acetylcholine receptors. Molecular Pharmacology 68: 1839–1851.

Kuryatov A, Onksen J and Lindstrom JM (2008) Roles of accessory subunits in α4β2* Nicotinic Receptors. Molecular Pharmacology 74: 132–143.

Labarca C, Schwarz J, Deshpande P et al. (2001) Point mutant mice with hypersensitive α4 nicotinic receptors show dopaminergic deficits and increased anxiety. Proceedings of the National Academy of Sciences of the USA 98: 2786–2791.

Lai M, Hughes EG, Peng X et al. (2009) AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Annals of Neurology 65: 424–434.

Luo J, Kuryatov A and Lindstrom J (2010) Specific immunotherapy of experimental myasthenia gravis by a novel mechanism. Annals of Neurology 67: 441–451.

Luo J, Taylor P, Losen M et al. (2009) Main immunogenic region structure promotes binding of conformation‐dependent myasthenia gravis autoantibodies, nicotinic acetylcholine receptor conformation maturation, and agonist sensitivity. Journal of Neuroscience 29: 13971–13980.

Manfredi I, Zani AD, Rampoldi L et al. (2009) Expression of mutant β2 nicotinic receptors during development is crucial for epileptogenesis. Human Molecular Genetics 18: 1075–1088.

Marubio LM, del Mar Arroyo‐Jimenez M, Cordero‐Erausquin M et al. (1999) Reduced antinociception in mice lacking neuronal nicotinic receptor subunits. Nature 398: 805–810.

Marubio LM, Gardier AM, Durier S et al. (2003) Effects of nicotine in the dopaminergic system of mice lacking the α4 subunit of neuronal nicotinic acetylcholine receptors. European Journal of Neuroscience 17: 1329–1337.

McKeon A, Lennon VA, Lachance DH, Fealey RD and Pittock SJ (2009) Ganglionic acetylcholine receptor autoantibody: oncological, neurological, and serological accompaniments. Archives of Neurology 66: 735–741.

Meriggioli MN and Sanders DB (2009) Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurology 8: 475–490.

Mexal S, Berger R, Logel J et al. (2010) Differential regulation of α7 nicotinic receptor gene (CHRNA7) expression in schizophrenic smokers. Journal of Molecular Neuroscience.

Nakauchi S, Brennan RJ, Boulter J and Sumikawa K (2007) Nicotine gates long‐term potentiation in the hippocampal CA1 region via the activation of α2* nicotinic ACh receptors. European Journal of Neuroscience 25: 2666–2681.

Niehusmann P, Dalmau J, Rudlowski C et al. (2009) Diagnostic value of N‐methyl‐d‐aspartate receptor antibodies in women with new‐onset epilepsy. Archives of Neurology 66: 458–464.

Olincy A, Harris JG, Johnson LL et al. (2006) Proof‐of‐concept trial of an α7 nicotinic agonist in schizophrenia. Archives of General Psychiatry 63: 630–638.

Orr‐Urtreger A, Broide RS, Kasten MR et al. (2000) Mice homozygous for the L250T mutation in the α7 nicotinic acetylcholine receptor show increased neuronal apoptosis and die within 1 day of birth. Journal of Neurochemistry 74: 2154–2166.

Orr‐Urtreger A, Goldner FM, Saeki M et al. (1997) Mice deficient in the α7 neuronal nicotinic acetylcholine receptor lack α‐bungarotoxin binding sites and hippocampal fast nicotinic currents. Journal of Neuroscience 17: 9165–9171.

Picciotto MR, Zoli M, Lena C et al. (1995) Abnormal avoidance learning in mice lacking functional high‐affinity nicotine receptor in the brain. Nature 374: 65–67.

Pons S, Fattore L, Cossu G et al. (2008) Crucial role of α4 and α6 nicotinic acetylcholine receptor subunits from ventral tegmental area in systemic nicotine self‐administration. Journal of Neuroscience 28: 12318–12327.

Rabenstein RL, Caldarone BJ and Picciotto MR (2006) The nicotinic antagonist mecamylamine has antidepressant‐like effects in wild‐type but not β2‐ or α7‐nicotinic acetylcholine receptor subunit knockout mice. Psychopharmacology 189: 395–401.

Rollema H, Hajos M, Seymour PA et al. (2009) Preclinical pharmacology of the α4β2 nAChR partial agonist varenicline related to effects on reward, mood and cognition. Biochemical Pharmacology 78: 813–824.

Ross SA, Wong JY, Clifford JJ et al. (2000) Phenotypic characterization of an α4 neuronal nicotinic acetylcholine receptor subunit knock‐out mouse. Journal of Neuroscience 20: 6431–6441.

Salas R, Orr‐Urtreger A, Broide RS et al. (2003) The nicotinic acetylcholine receptor subunit α5 mediates short‐term effects of nicotine in vivo. Molecular Pharmacology 63: 1059–1066.

Salminen O, Drapeau JA, McIntosh JM et al. (2007) Pharmacology of α‐conotoxin MII‐sensitive subtypes of nicotinic acetylcholine receptors isolated by breeding of null mutant mice. Molecular Pharmacology 71: 1563–1571.

Tapper AR, McKinney SL, Nashmi R et al. (2004) Nicotine activation of α4* receptors: sufficient for reward, tolerance, and sensitization. Science 306: 1029–1032.

Teper Y, Whyte D, Cahir E et al. (2007) Nicotine‐induced dystonic arousal complex in a mouse line harboring a human autosomal‐dominant nocturnal frontal lobe epilepsy mutation. Journal of Neuroscience 27: 10128–10142.

Tumkosit P, Kuryatov A, Luo J and Lindstrom J (2006) β3 Subunits promote expression and nicotine‐induced up‐regulation of human nicotinic α6* nicotinic acetylcholine receptors expressed in transfected cell lines. Molecular Pharmacology 70: 1358–1368.

Unwin N (2005) Refined structure of the nicotinic acetylcholine receptor at 4A resolution. Journal of Molecular Biology 346: 967–989.

Vernino S, Lindstrom J, Hopkins S, Wang Z and Low PA (2008) Characterization of ganglionic acetylcholine receptor autoantibodies. Journal of Neuroimmunology 197: 63–69.

Vetter DE, Liberman MC, Mann J et al. (1999) Role of α9 nicotinic ACh receptor subunits in the development and function of cochlear efferent innervation. Neuron 23: 93–103.

Whiteaker P, Wilking JA, Brown RW et al. (2009) Pharmacological and immunochemical characterization of α2* nicotinic acetylcholine receptors (nAChRs) in mouse brain. Acta Pharmacologica Sinica 30: 795–804.

Xu W, Gelber S, Orr‐Urtreger A et al. (1999a) Megacystis, mydriasis, and ion channel defect in mice lacking the α3 neuronal nicotinic acetylcholine receptor. Proceedings of the National Academy of Sciences of the USA 96: 5746–5751.

Xu W, Orr‐Urtreger A, Nigro F et al. (1999b) Multiorgan autonomic dysfunction in mice lacking the β2 and the β4 subunits of neuronal nicotinic acetylcholine receptors. Journal of Neuroscience 19: 9298–9305.

Zoli M, Picciotto MR, Ferrari R, Cocchi D and Changeux JP (1999) Increased neurodegeneration during ageing in mice lacking high‐affinity nicotine receptors. EMBO Journal 18: 1235–1244.

Further Reading

Benowitz NL (2008) Neurobiology of nicotine addiction: implications for smoking cessation treatment. American Journal of Medicine 121: S3–S10.

Bertrand D, Gopalakrishnan M and Donnelly Roberts D (2009) Nicotinic acetylcholine receptors as therapeutic targets: emerging frontiers in basic research and clinical science–editorial perspective. Biochemical Pharmacology (Special Issue) 78: 657–925.

Engel AG, Shen XM, Selcen D and Sine SM (2010) What have we learned from the congenital myasthenic syndromes. Journal of Molecular Neuroscience 40: 143–153.

Gotti C, Moretti M, Gaimarri A et al. (2007) Heterogeneity and complexity of native brain nicotinic receptors. Biochemical Pharmacology 74: 1102–1111.

Millar NS and Gotti C (2009) Diversity of vertebrate nicotinic acetylcholine receptors. Neuropharmacology 56: 237–246.

Picciotto MR, Addy NA, Mineur YS and Brunzell DH (2008) It is not “either/or”: activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood. Progress in Neurobiology 84: 329–342.

Steinlein OK (2004) Genetic mechanisms that underlie epilepsy. Nature Reviews. Neuroscience 5: 400–408.

Taly A, Corringer PJ, Guedin D, Lestage P and Changeux JP (2009) Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system. Nature Reviews. Drug Discovery 8: 733–750.

Vincent A, Lang B and Kleopa KA (2006) Autoimmune channelopathies and related neurological disorders. Neuron 52: 123–138.

Zouridakis M, Zisimopoulou P, Poulas K and Tzartos SJ (2009) Recent advances in understanding the structure of nicotinic acetylcholine receptors. IUBMB Life 61: 407–423.

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Lindstrom, Jon(Sep 2010) Nicotinic Acetylcholine Receptors. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000245.pub2]