Nicotinic Receptors

Abstract

Fast neurotransmission in the central and peripheral nervous systems is mediated by the activity of ligand‐gated ion channels. Nicotinic acetylcholine receptors (nAChRs) belong to the family of cation‐permeable channels and result from the assembly of five subunits that form both the ligand‐binding site and the ionic pore. Sixteen genes encoding for these receptors have been identified in mammals and show differential expression throughout the body. Endogenously activated by ACh, nAChRs are the primary target of nicotine contained in tobacco leaves and mediate its addiction. The use of a partial agonist of nicotinic receptors significantly reduces craving and show good outcomes in smoking cessation. Spontaneous variations occurring in the genes encoding for nAChRs are associated with neurological diseases such as myasthenia gravis, to genetically transmissible epilepsies and to nicotine dependence. Dysfunction of the nAChR transmission is associated with diseases including schizophrenia, autism and neurodegenerative diseases such as Alzheimer's. Small molecules have recently shown beneficial outcomes in Alzheimer disease opening new avenues to treat neurological affections.

Key Concepts:

  • Neurotransmission is mediated by integral membrane proteins and can be subdivided into ligand‐gated ion channels and G‐coupled proteins.

  • Nicotinic acetylcholine receptors belong to the family of cationic ligand‐gated ion channels that comprises four transmembrane domains and result from the assembly of five subunit around an axis of pseudosymmetry.

  • Nicotinic acetylcholine receptors are key players in nicotine addiction and the primary target for this natural alkaloid that is contained in tobacco leaves.

  • Nicotinic acetylcholine receptors at the neuromuscular junction play a determinant role in mediating transmission from the motor nerve to the muscle cell. Impairment of these receptor function leads to myasthenia gravis, which can be decomposed in its most common form to an autoimmune disease and in rarer forms in mutations of one or more genes.

  • Dysfunction of the cholinergic system is associated with cognitive impairment and with neurological diseases such as schizophrenia, autism, genetically transmissible epilepsies and neurodegenerative diseases such as Alzheimer's.

  • The development of small chemical molecules such as the partial agonist varenicline is shown to help in smoking cessation programmes and, more recently, for α7 EVP‐6124 in the treatment of Alzheimer disease.

Keywords: synaptic transmission; neurotransmitter; receptors; brain; ligand‐gated channels

Figure 1.

Protein structure of nicotinic receptors: (a) Alignment of human α4, β2 and α7 polypeptides with exon numbering and splicing positions indicated by arrows. Abbreviation: SP, signal peptide. TM I–TM IV indicate the position of the four transmembrane domains. The open box between the SP and TM1 symbolises the cysteine loop and the two adjacent cysteines on the α4 and α7 subunits. (b) Schematic three‐dimensional representation of the receptor inserted into the membrane. (c) High‐resolution protein structure obtained from crystallography showing the soluble acetylcholine‐binding protein (ACHBP) and the two four transmembrane bacterial proteins ELIC and GLIC. These structures were kindly provided by Dr. C. Ulens (Leuven University).

Figure 2.

(a) Human karyotype and localisation of the known nicotinic receptor genes. Note the β4, α3 and α5 gene clusters on chromosome 15. The position of the α7 and the duplicated α7 exons 5–10 (dupα7) are represented on the same chromosome 15. Genes coding for the muscle receptor subunits are localised on chromosomes 2 and 17. (b) Muscle and neuronal gene subunits with their respective positions and accession numbers. Structures were kindly provided by Prof. O.K. Steinlein.

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Further Reading

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Bertrand D and Changeux JP (1995) Nicotinic receptor: an allosteric protein specialized for intercellular communication. Seminars in Neuroscience 7: 75–90.

Dani JA (2001) Overview of nicotinic receptors and their roles in the central nervous system. Biological Psychiatry 49: 166–174.

Le Novere N and Changeux JP (1999) The ligand gated ion channel database. Nucleic Acids Research 27: 340–342.

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Web Links

http://bodymap.ims.u‐tokyo.ac.jp. BodyMap

Division of Medical Genetics, University of Geneva. http://medgen.unige.ch/research/ts65dn/index.html

Cholinergic receptor, nicotinic, alpha polypeptide 1 (muscle) (CHRNA1); Locus ID: 1134. LocusLink. http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=1134

Cholinergic receptor, nicotinic, alpha polypeptide 7 (CHRNA7); Locus ID: 1139. LocusLink. http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=1139

Cholinergic receptor, nicotinic, beta polypeptide 4 (CHRNB4); Locus ID: 1143. LocusLink. http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=1143

Cholinergic receptor, nicotinic, alpha polypeptide 1 (muscle) (CHRNA1); MIM number: 100690. OMIM. http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?100690

Cholinergic receptor, nicotinic, alpha polypeptide 7 (CHRNA7); MIM number: 118511. OMIM. http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?118511

Cholinergic receptor, nicotinic, beta polypeptide 4 (CHRNB4); MIM number: 118509. OMIM. http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?118509

Institut Pasteur Receptors and Cognition Laboratory. http://www.pasteur.fr/recherche/unites/neubiomol/

Nicotine and the Nervous System. http://www.geocities.com/CapeCanaveral/2257/nictop.html

NCBI Genes and Disease. http://www.ncbi.nlm.nih.gov/disease/

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How to Cite close
Marger, Laurine, Itier, Valérie, and Bertrand, Daniel(Feb 2014) Nicotinic Receptors. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005057.pub2]