Nicotinic Acetylcholine Receptors


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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Further Reading

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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.

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