Nicotinic Receptors


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.



Bertrand D, Galzi JL, Devillers‐Thiéry A, Bertrand S and Changeux JP (1993) Stratification of the channel domain in neurotransmitter receptors. Current Opinion in Cell Biology 5(4): 688–693.

Bocquet N, Nury H, Baaden M et al. (2009) X‐ray structure of a pentameric ligand‐gated ion channel in an apparently open conformation. Nature 457(7225): 111–114.

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(6835): 269–276.

Calimet N, Simoes M, Changeux JP et al. (2013) A gating mechanism of pentameric ligand‐gated ion channels. Proceedings of the National Academy of Sciences of the USA 110(42): E3987–E3996.

Couturier S, Bertrand D, Matter JM et al. (1990) A neuronal nicotinic acetylcholine receptor subunit (alpha 7) is developmentally regulated and forms a homo‐oligomeric channel blocked by alpha‐BTX. Neuron 5(6): 847–856.

Dani JA and Bertrand D (2007) Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system. Annual Review of Pharmacology and Toxicology 47: 699–729.

De Fusco M, Becchetti A, Patrignani A et al. (2000) The nicotinic receptor beta 2 subunit is mutant in nocturnal frontal lobe epilepsy. Nature Genetics 26(3): 275–276.

Elgoyhen AB, Johnson DS, Boulter J, Vetter DE and Heinemann S (1994) Alpha 9: an acetylcholine receptor with novel pharmacological properties expressed in rat cochlear hair cells. Cell 79(4): 705–715.

Gault J, Robinson M, Berger R et al. (1998) Genomic organization and partial duplication of the human alpha7 neuronal nicotinic acetylcholine receptor gene (CHRNA7). Genomics 52(2): 173–185.

Guillem K, Bloem B, Poorthuis RB et al. (2011) Nicotinic acetylcholine receptor β2 subunits in the medial prefrontal cortex control attention. Science 333(6044): 888–891.

Hilf RJ and Dutzler R (2008) X‐ray structure of a prokaryotic pentameric ligand‐gated ion channel. Nature 452(7185): 375–379.

Khakh BS, Zhou X, Sydes J, Galligan JJ and Lester HA (2000) State‐dependent cross‐inhibition between transmitter‐gated cation channels. Nature 406(6794): 405–410.

Lacaze E, Gruchy N, Penniello‐Valette MJ et al. (2013) De novo 15q13.3 microdeletion with cryptogenic West syndrome. American Journal of Medical Genetics Part A 161(10): 2582–2587.

Leonard S and Bertrand D (2001) Neuronal nicotinic receptors: from structure to function. Nicotine & Tobacco Research 3(3): 203–223.

Lepichon JB, Bittel DC, Graf WD and Yu S (2010) A 15q13.3 homozygous microdeletion associated with a severe neurodevelopmental disorder suggests putative functions of the TRPM1, CHRNA7, and other homozygously deleted genes. American Journal of Medical Genetics Part A 152A(5): 1300–1304.

Le Pichon JB, Yu S, Kibiryeva N, Graf WD and Bittel DC (2013) Genome‐wide gene expression in a patient with 15q13.3 homozygous microdeletion syndrome. European Journal of Human Genetics 21(10): 1093–1099.

Liao J, DeWard SJ, Madan‐Khetarpal S, Surti U and Hu J (2011) A small homozygous microdeletion of 15q13.3 including the CHRNA7 gene in a girl with a spectrum of severe neurodevelopmental features. American Journal of Medical Genetics Part A 155A(11): 2795–2800.

Miyazawa A, Fujiyoshi Y, Stowell M and Unwin N (1999) Nicotinic acetylcholine receptor at 4.6 A resolution: transverse tunnels in the channel wall. Journal of Molecular Biology 288(4): 765–786.

Phillips HA, Favre I, Kirkpatrick M et al. (2001) CHRNB2 is the second acetylcholine receptor subunit associated with autosomal dominant nocturnal frontal lobe epilepsy. American Journal of Medical Genetics 68(1): 225–231.

Prickaerts J, van Goethem NP, Chesworth R et al. (2011) EVP‐6124, a novel and selective α7 nicotinic acetylcholine receptor partial agonist, improves memory performance by potentiating the acetylcholine response of α7 nicotinic acetylcholine receptors. Neuropharmacology 62(2): 1099–1110.

Radcliffe KA and Dani JA (1998) Nicotinic stimulation produces multiple forms of increased glutamatergic synaptic transmission. Journal of Neuroscience 18(18): 7075–7083.

Steinlein OK and Bertrand D (2010) Nicotinic receptor channelopathies and epilepsy. Pflügers Archiv 460(2): 495–503.

Steinlein OK, Mulley JC, Propping P et al. (1995) A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nature Genetics 11(2): 201–203.

Temburni MK, Blitzblau RC and Jacob MH (2000) Receptor targeting and heterogeneity at interneuronal nicotinic cholinergic synapses in vivo. Journal of Physiology 525(Pt 1): 21–29.

Tracey KJ (2011) Cell biology. Ancient neurons regulate immunity. Science 332(6030): 673–674.

Yang Y, Paspalas CD, Jin LE et al. (2013) Nicotinic α7 receptors enhance NMDA cognitive circuits in dorsolateral prefrontal cortex. Proceedings of the National Academy of Sciences of the USA 110(29): 12078–12083.

Further Reading

Alkondon M, Reinhardt S, Lobron C et al. (1994) Diversity of nicotinic acetylcholine receptors in rat hippocampal neurons. II. The rundown and inward rectification of agonist‐elicited whole‐cell currents and identification of receptor subunits by in situ hybridization. Journal of Pharmacology and Experimental Therapy 271: 494–506.

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.

MacDermott AB, Role LW and Siegelbaum SA (1999) Presynaptic ionotropic receptors and the control of transmitter release. Annual Review of Neuroscience 22: 443–485.

Sargent PB (1993) The diversity of neuronal nicotinic acetylcholine receptors. Annual Review of Neuroscience 16: 403–443.

Wonnacott S (1997) Presynaptic nicotinic ACh receptors. Trends in Neuroscience 20: 92–98.

Web Links

http://bodymap.ims.u‐ BodyMap

Division of Medical Genetics, University of Geneva.

Cholinergic receptor, nicotinic, alpha polypeptide 1 (muscle) (CHRNA1); Locus ID: 1134. LocusLink.

Cholinergic receptor, nicotinic, alpha polypeptide 7 (CHRNA7); Locus ID: 1139. LocusLink.

Cholinergic receptor, nicotinic, beta polypeptide 4 (CHRNB4); Locus ID: 1143. LocusLink.

Cholinergic receptor, nicotinic, alpha polypeptide 1 (muscle) (CHRNA1); MIM number: 100690. OMIM.‐post/Omim/dispmim?100690

Cholinergic receptor, nicotinic, alpha polypeptide 7 (CHRNA7); MIM number: 118511. OMIM.‐post/Omim/dispmim?118511

Cholinergic receptor, nicotinic, beta polypeptide 4 (CHRNB4); MIM number: 118509. OMIM.‐post/Omim/dispmim?118509

Institut Pasteur Receptors and Cognition Laboratory.

Nicotine and the Nervous System.

NCBI Genes and 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. [doi: 10.1002/9780470015902.a0005057.pub2]