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.