Nicotinic acetylcholine receptor

{{short description|Acetylcholine receptors named for their selective binding of nicotine}} [[Image:Acetylcholine.svg|thumb|Acetylcholine]] [[Image:Nicotine.svg|thumb|Nicotine]]

'''Nicotinic acetylcholine receptors''', or '''nAChRs''', are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral nervous system, muscle, and many other tissues of many organisms. At the neuromuscular junction they are the primary receptor in muscle for motor nerve-muscle communication that controls muscle contraction. In the peripheral nervous system: (1) they transmit outgoing signals from the presynaptic to the postsynaptic cells within the sympathetic and parasympathetic nervous system; and (2) they are the receptors found on skeletal muscle that receives acetylcholine released to signal for muscular contraction. In the immune system, nAChRs regulate inflammatory processes and signal through distinct intracellular pathways.<ref>{{cite journal | vauthors = Lu B, Kwan K, Levine YA, Olofsson PS, Yang H, Li J, Joshi S, Wang H, Andersson U, Chavan SS, Tracey KJ | display-authors = 6 | title = α7 nicotinic acetylcholine receptor signaling inhibits inflammasome activation by preventing mitochondrial DNA release | journal = Molecular Medicine | volume = 20 | issue = 1 | pages = 350–8 | date = August 2014 | pmid = 24849809 | pmc = 4153835 | doi = 10.2119/molmed.2013.00117 }}</ref> In insects, the cholinergic system is limited to the central nervous system.<ref name=Yamamoto1>{{cite book |doi=10.1007/978-4-431-67933-2_1 |chapter=Nicotine to Nicotinoids: 1962 to 1997 |title=Nicotinoid Insecticides and the Nicotinic Acetylcholine Receptor |year=1999 |last1=Yamamoto |first1=Izuru | name-list-style = vanc |pages=3–27 |isbn=978-4-431-68011-6 }}</ref>

The nicotinic receptors are considered cholinergic receptors, because they respond to acetylcholine. Nicotinic receptors get their name from nicotine, which selectively binds to nicotinic receptors but not to other acetylcholine receptors.<ref name="Purves" /><ref name="Siegel">{{cite book| vauthors = Siegel GJ, Agranoff BW, Fisher SK, Albers RW, Uhler MD | year=1999 | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK28090/ | title=Basic Neurochemistry: Molecular, Cellular and Medical Aspects | chapter=GABA Receptor Physiology and Pharmacology | edition= 6th | publisher=American Society for Neurochemistry | access-date= 2008-10-01}}</ref><ref name="Itier">{{cite journal | vauthors = Itier V, Bertrand D | title = Neuronal nicotinic receptors: from protein structure to function | journal = FEBS Letters | volume = 504 | issue = 3 | pages = 118–25 | date = August 2001 | pmid = 11532443 | doi = 10.1016/s0014-5793(01)02702-8 | doi-access = free | bibcode = 2001FEBSL.504..118I }}</ref> (The other type of acetylcholine receptor, the muscarinic receptor, likewise gets its name from a chemical that selectively attaches to that receptor: muscarine.<ref name="pmid17073660">{{cite journal | vauthors = Ishii M, Kurachi Y | title = Muscarinic acetylcholine receptors | journal = Current Pharmaceutical Design | volume = 12 | issue = 28 | pages = 3573–81 | date = 1 October 2006 | pmid = 17073660 | doi = 10.2174/138161206778522056 }}</ref> Acetylcholine itself binds to both muscarinic and nicotinic acetylcholine receptors.<ref name="Cholinergic Toxicity">{{cite book |last1=Lott |first1=Erica L. |last2=Jones |first2=Elizabeth B. | name-list-style = vanc |title=StatPearls |date=2020 |publisher=StatPearls Publishing |url=https://www.ncbi.nlm.nih.gov/books/NBK539783/ |chapter=Cholinergic Toxicity |pmid=30969605 }}</ref>)

As ionotropic receptors, nAChRs are directly linked to ion channels. Some evidence suggests that these receptors can also use second messengers (as metabotropic receptors do) in some cases.<ref>{{cite journal | vauthors = Kabbani N, Nordman JC, Corgiat BA, Veltri DP, Shehu A, Seymour VA, Adams DJ | title = Are nicotinic acetylcholine receptors coupled to G proteins? | journal = BioEssays | volume = 35 | issue = 12 | pages = 1025–34 | date = December 2013 | pmid = 24185813 | doi = 10.1002/bies.201300082 | s2cid = 9441100 }}</ref> Nicotinic acetylcholine receptors are the best-studied of the ionotropic receptors.<ref name="Purves" >{{cite book | last1 = Purves | first1 = Dale | first2 = George J. | last2 = Augustine | first3 = David | last3 = Fitzpatrick | first4 = William C. | last4 = Hall | first5 = Anthony-Samuel | last5 = LaMantia | first6 = James O. | last6 = McNamara | first7 = Leonard E. | last7 = White | name-list-style = vanc | title = Neuroscience | url = https://archive.org/details/neuroscienceissu00purv | url-access = limited | edition = 4th | publisher = Sinauer Associates | pages = [https://archive.org/details/neuroscienceissu00purv/page/n147 122]–6 | year = 2008 | isbn = 978-0-87893-697-7}}</ref>

Since nicotinic receptors help transmit outgoing signals for the sympathetic and parasympathetic systems, nicotinic receptor antagonists such as hexamethonium interfere with the transmission of these signals. Thus, for example, nicotinic receptor antagonists interfere with the baroreflex<ref>{{cite journal | vauthors = Henderson CG, Ungar A | title = Effect of cholinergic antagonists on sympathetic ganglionic transmission of vasomotor reflexes from the carotid baroreceptors and chemoreceptors of the dog. | journal = The Journal of Physiology | volume = 277 | issue = 1 | pages = 379–385 | date = April 1978 | doi = 10.1113/jphysiol.1978.sp012278 | pmid = 206690 | pmc = 1282395 | doi-access = free}}</ref> that normally corrects changes in blood pressure by sympathetic and parasympathetic stimulation of the heart.

== Structure == thumb|Nicotinic receptor structure Nicotinic receptors, with a molecular mass of 290 kDa,<ref name="Unwin">{{cite journal | vauthors = Unwin N | title = Refined structure of the nicotinic acetylcholine receptor at 4A resolution | journal = Journal of Molecular Biology | volume = 346 | issue = 4 | pages = 967–89 | date = March 2005 | pmid = 15701510 | doi = 10.1016/j.jmb.2004.12.031 }}</ref> are made up of five subunits, arranged symmetrically around a central pore.<ref name="Purves" /> Each subunit comprises four transmembrane domains with both the N- and C-terminus located extracellularly. They possess similarities with GABA_A receptors, glycine receptors, and the type 3 serotonin receptors (which are all ionotropic receptors), or the signature Cys-loop proteins.<ref name="Cascio">{{cite journal | vauthors = Cascio M | title = Structure and function of the glycine receptor and related nicotinicoid receptors | journal = The Journal of Biological Chemistry | volume = 279 | issue = 19 | pages = 19383–6 | date = May 2004 | pmid = 15023997 | doi = 10.1074/jbc.R300035200 | doi-access = free }}</ref>

In vertebrates, nicotinic receptors are broadly classified into two subtypes based on their primary sites of expression: ''muscle-type'' nicotinic receptors and ''neuronal-type'' nicotinic receptors. In the muscle-type receptors, found at the neuromuscular junction, receptors are either the embryonic form, composed of α₁, β₁, γ, and δ subunits in a 2:1:1:1 ratio ((α₁)₂β₁γδ), or the adult form composed of α₁, β₁, δ, and ε subunits in a 2:1:1:1 ratio ((α₁)₂β₁δε).<ref name="Purves" /><ref name="Siegel"/><ref name="Itier"/><ref name="Giniatullin">{{cite journal | vauthors = Giniatullin R, Nistri A, Yakel JL | title = Desensitization of nicotinic ACh receptors: shaping cholinergic signaling | journal = Trends in Neurosciences | volume = 28 | issue = 7 | pages = 371–8 | date = July 2005 | pmid = 15979501 | doi = 10.1016/j.tins.2005.04.009 | s2cid = 19114228 }}</ref> The neuronal subtypes are various homomeric (all one type of subunit) or heteromeric (at least one α and one β) combinations of twelve different nicotinic receptor subunits: α₂−α₁₀ and β₂−β₄. Examples of the neuronal subtypes include: (α₄)₃(β₂)₂, (α₄)₂(β₂)₃, (α₃)₂(β₄)₃, α₄α₆β₃(β₂)₂, (α₇)₅, and many others. In both muscle-type and neuronal-type receptors, the subunits are very similar to one another, especially in the hydrophobic regions.<ref name=":0" />

A number of electron microscopy and x-ray crystallography studies have provided very high resolution structural information for muscle and neuronal nAChRs and their binding domains.<ref name="Unwin"/><ref>{{cite journal | vauthors = Brejc K, van Dijk WJ, Klaassen RV, Schuurmans M, van Der Oost J, Smit AB, Sixma TK | title = Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors | journal = Nature | volume = 411 | issue = 6835 | pages = 269–76 | date = May 2001 | pmid = 11357122 | doi = 10.1038/35077011 | bibcode = 2001Natur.411..269B | s2cid = 4415937 }}</ref><ref>{{cite journal | vauthors = Zouridakis M, Giastas P, Zarkadas E, Chroni-Tzartou D, Bregestovski P, Tzartos SJ | title = Crystal structures of free and antagonist-bound states of human α9 nicotinic receptor extracellular domain | journal = Nature Structural & Molecular Biology | volume = 21 | issue = 11 | pages = 976–80 | date = November 2014 | pmid = 25282151 | doi = 10.1038/nsmb.2900 | s2cid = 30096256 }}</ref><ref>{{cite journal | vauthors = Morales-Perez CL, Noviello CM, Hibbs RE | title = X-ray structure of the human α4β2 nicotinic receptor | journal = Nature | volume = 538 | issue = 7625 | pages = 411–415 | date = October 2016 | pmid = 27698419 | pmc = 5161573 | doi = 10.1038/nature19785 | bibcode = 2016Natur.538..411M }}</ref>

==Binding== {{About||ligands|Nicotinic agonist|and|Nicotinic antagonist}}

As with all ligand-gated ion channels, opening of the nAChR channel pore requires the binding of a chemical messenger. Several different terms are used to refer to the molecules that bind receptors, such as ligand, agonist, or transmitter. As well as the endogenous agonist acetylcholine, agonists of the nAChR include nicotine, epibatidine, and choline. Nicotinic antagonists that block the receptor include mecamylamine, dihydro-β-erythroidine, α-bungarotoxin, and hexamethonium.<ref name=":0">{{Cite journal |last1=Matera |first1=Carlo |last2=Papotto |first2=Claudio |last3=Dallanoce |first3=Clelia |last4=De Amici |first4=Marco |date=August 2023 |title=Advances in small molecule selective ligands for heteromeric nicotinic acetylcholine receptors |url=https://linkinghub.elsevier.com/retrieve/pii/S104366182300169X |journal=Pharmacological Research |volume=194 |article-number=106813 |doi=10.1016/j.phrs.2023.106813|pmid=37302724 |hdl=2434/978688 |hdl-access=free }}</ref><ref>{{Cite journal |last1=Young |first1=Howard S. |last2=Herbette |first2=Leo G. |last3=Skita |first3=Victor |date=August 2003 |title=Alpha-bungarotoxin binding to acetylcholine receptor membranes studied by low angle X-ray diffraction |journal=Biophysical Journal |volume=85 |issue=2 |pages=943–953 |doi=10.1016/S0006-3495(03)74533-0 |issn=0006-3495 |pmc=1303215 |pmid=12885641|bibcode=2003BpJ....85..943Y }}</ref>

In muscle-type nAChRs, the acetylcholine binding sites are located at the α and either ε or δ subunits interface. In neuronal nAChRs, the binding site is located at the interface of an α and a β subunit or between two α subunits in the case of α₇ receptors. The binding site is located in the extracellular domain near the N terminus.<ref name="Siegel"/><ref>{{cite book|last=Squire|first=Larry | name-list-style = vanc |title=Fundamental neuroscience |year=2003| publisher=Acad. Press|location=Amsterdam|isbn=978-0-12-660303-3|page=1426|edition= 2nd}}</ref> When an agonist binds to the site, all present subunits undergo a conformational change and the channel is opened<ref name="Colquhoun">{{cite journal | vauthors = Colquhoun D, Sivilotti LG | title = Function and structure in glycine receptors and some of their relatives | journal = Trends in Neurosciences | volume = 27 | issue = 6 | pages = 337–44 | date = June 2004 | pmid = 15165738 | doi = 10.1016/j.tins.2004.04.010 | citeseerx = 10.1.1.385.3809 | s2cid = 19008547 }}</ref> and a pore with a diameter of about 0.65&nbsp;nm opens.<ref name="Siegel"/>

==Channel opening== Nicotinic AChRs may exist in different interconvertible conformational states. Binding of an agonist stabilizes the open and desensitized states. In normal physiological conditions, the receptor needs exactly two molecules of ACh to open.<ref>{{Cite book|title=The physiology of excitable cells| last = Aidley | first = David J | name-list-style = vanc |date=1998|publisher=Cambridge University Press|isbn=978-0-521-57415-0|edition=4th|location=Cambridge, UK|oclc=38067558|url-access=registration|url=https://archive.org/details/physiologyofexci0000aidl_s5u8}}{{page needed|date=April 2020}}</ref> Opening of the channel allows positively charged ions to move across it; in particular, sodium enters the cell and potassium exits. The net flow of positively charged ions is inward.

The nAChR is a non-selective cation channel, meaning that several different positively charged ions can cross through.<ref name="Purves" /> It is permeable to Na⁺ and K⁺, with some subunit combinations that are also permeable to Ca²⁺.<ref name="Siegel" /><ref name="Beker_AChR_Ca2+">{{cite journal | vauthors = Beker F, Weber M, Fink RH, Adams DJ | title = Muscarinic and nicotinic ACh receptor activation differentially mobilize Ca2+ in rat intracardiac ganglion neurons | journal = Journal of Neurophysiology | volume = 90 | issue = 3 | pages = 1956–64 | date = September 2003 | pmid = 12761283 | doi = 10.1152/jn.01079.2002 | s2cid = 8684707 }}</ref><ref name="Weber_nAChR_anaesthetics">{{cite journal | vauthors = Weber M, Motin L, Gaul S, Beker F, Fink RH, Adams DJ | title = Intravenous anesthetics inhibit nicotinic acetylcholine receptor-mediated currents and Ca2+ transients in rat intracardiac ganglion neurons | journal = British Journal of Pharmacology | volume = 144 | issue = 1 | pages = 98–107 | date = January 2005 | pmid = 15644873 | pmc = 1575970 | doi = 10.1038/sj.bjp.0705942 }}</ref> The amount of sodium and potassium the channels allow through their pores (their conductance) varies from 50 to 110&nbsp;pS, with the conductance depending on the specific subunit composition as well as the permeant ion.<ref name="Mishina">{{cite journal | vauthors = Mishina M, Takai T, Imoto K, Noda M, Takahashi T, Numa S, Methfessel C, Sakmann B | display-authors = 6 | title = Molecular distinction between fetal and adult forms of muscle acetylcholine receptor | journal = Nature | volume = 321 | issue = 6068 | pages = 406–11 | date = May 1986 | pmid = 2423878 | doi = 10.1038/321406a0 | bibcode = 1986Natur.321..406M | s2cid = 4356336 }}</ref>

Many neuronal nAChRs can affect the release of other neurotransmitters.<ref name="Itier" /> The channel usually opens rapidly and tends to remain open until the agonist diffuses away, which usually takes about 1 millisecond.<ref name="Siegel" /> AChRs can spontaneously open with no ligands bound or can spontaneously close with ligands bound, and mutations in the channel can shift the likelihood of either event.<ref>{{cite journal | vauthors = Einav T, Phillips R | title = Monod-Wyman-Changeux Analysis of Ligand-Gated Ion Channel Mutants | journal = The Journal of Physical Chemistry B | volume = 121 | issue = 15 | pages = 3813–3824 | date = April 2017 | pmid = 28134524 | pmc = 5551692 | doi = 10.1021/acs.jpcb.6b12672 | arxiv = 1701.06122 | bibcode = 2017arXiv170106122E }}</ref><ref name="Colquhoun"/> Therefore, ACh binding changes the probability of pore opening, which increases as more ACh binds.

The nAChR is unable to bind ACh when bound to any of the snake venom α-neurotoxins. These α-neurotoxins antagonistically bind tightly and noncovalently to nAChRs of skeletal muscles and in neurons, thereby blocking the action of ACh at the postsynaptic membrane, inhibiting ion flow and leading to paralysis and death. The nAChR contains two binding sites for snake venom neurotoxins. Progress in discovering the dynamics of binding action of these sites has proved difficult, although recent studies using normal mode dynamics<ref>{{cite journal | vauthors = Levitt M, Sander C, Stern PS | title = Protein normal-mode dynamics: trypsin inhibitor, crambin, ribonuclease and lysozyme | journal = Journal of Molecular Biology | volume = 181 | issue = 3 | pages = 423–47 | date = February 1985 | pmid = 2580101 | doi = 10.1016/0022-2836(85)90230-x }}</ref> have aided in predicting the nature of both the binding mechanisms of snake toxins and of ACh to nAChRs. These studies have shown that a twist-like motion caused by ACh binding is likely responsible for pore opening, and that one or two molecules of α-bungarotoxin (or other long-chain α-neurotoxin) suffice to halt this motion. The toxins seem to lock together neighboring receptor subunits, inhibiting the twist and therefore, the opening motion.<ref>{{cite journal | vauthors = Samson AO, Levitt M | title = Inhibition mechanism of the acetylcholine receptor by alpha-neurotoxins as revealed by normal-mode dynamics | journal = Biochemistry | volume = 47 | issue = 13 | pages = 4065–70 | date = April 2008 | pmid = 18327915 | pmc = 2750825 | doi = 10.1021/bi702272j }}</ref>

==Effects== The activation of receptors by nicotine modifies the state of neurons through two main mechanisms. On one hand, the movement of cations causes a depolarization of the plasma membrane (which results in an excitatory postsynaptic potential in neurons) leading to the activation of voltage-gated ion channels. On the other hand, the entry of calcium acts, either directly or indirectly, on different intracellular cascades. This leads, for example, to the regulation of activity of some genes or the release of neurotransmitters.{{citation needed|date=April 2020}}

==Regulation==

===Desensitization===

Ligand-bound desensitization of receptors was first characterized by Katz and Thesleff in the nicotinic acetylcholine receptor.<ref name="P1983">{{cite journal | vauthors = Pitchford S, Day JW, Gordon A, Mochly-Rosen D | title = Nicotinic acetylcholine receptor desensitization is regulated by activation-induced extracellular adenosine accumulation | journal = The Journal of Neuroscience | volume = 12 | issue = 11 | pages = 4540–4 | date = November 1992 | pmid = 1331363 | pmc = 6576003 | doi = 10.1523/JNEUROSCI.12-11-04540.1992 }}</ref>

Prolonged or repeated exposure to a stimulus often results in decreased responsiveness of that receptor toward a stimulus, termed desensitization. nAChR function can be modulated by phosphorylation<ref name="pmid6302672">{{cite journal | vauthors = Huganir RL, Greengard P | title = cAMP-dependent protein kinase phosphorylates the nicotinic acetylcholine receptor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 80 | issue = 4 | pages = 1130–4 | date = February 1983 | pmid = 6302672 | pmc = 393542 | doi = 10.1073/pnas.80.4.1130 | bibcode = 1983PNAS...80.1130H | doi-access = free }}</ref> by the activation of second messenger-dependent protein kinases. PKA<ref name=P1983/> and PKC,<ref name="pmid3038884">{{cite journal | vauthors = Safran A, Sagi-Eisenberg R, Neumann D, Fuchs S | title = Phosphorylation of the acetylcholine receptor by protein kinase C and identification of the phosphorylation site within the receptor delta subunit | journal = The Journal of Biological Chemistry | volume = 262 | issue = 22 | pages = 10506–10 | date = August 1987 | doi = 10.1016/S0021-9258(18)60990-1 | pmid = 3038884 | doi-access = free }}</ref> as well as tyrosine kinases,<ref>{{cite journal | vauthors = Hopfield JF, Tank DW, Greengard P, Huganir RL | title = Functional modulation of the nicotinic acetylcholine receptor by tyrosine phosphorylation | journal = Nature | volume = 336 | issue = 6200 | pages = 677–80 | date = December 1988 | pmid = 3200319 | doi = 10.1038/336677a0 | bibcode = 1988Natur.336..677H | s2cid = 4239105 }}</ref> have been shown to phosphorylate the nAChR resulting in its desensitization. It has been reported that, after prolonged receptor exposure to the agonist, the agonist itself causes an agonist-induced conformational change in the receptor, resulting in receptor desensitization.<ref name="pmid712829">{{cite journal | vauthors = Barrantes FJ | title = Agonist-mediated changes of the acetylcholine receptor in its membrane environment | journal = Journal of Molecular Biology | volume = 124 | issue = 1 | pages = 1–26 | date = September 1978 | pmid = 712829 | doi = 10.1016/0022-2836(78)90144-4 }}</ref>

Desensitized receptors can revert to a prolonged open state when an agonist is bound in the presence of a positive allosteric modulator, for example PNU-120,596.<ref name="pmid15858066">{{cite journal | vauthors = Hurst RS, Hajós M, Raggenbass M, Wall TM, Higdon NR, Lawson JA, Rutherford-Root KL, Berkenpas MB, Hoffmann WE, Piotrowski DW, Groppi VE, Allaman G, Ogier R, Bertrand S, Bertrand D, Arneric SP | display-authors = 6 | title = A novel positive allosteric modulator of the alpha7 neuronal nicotinic acetylcholine receptor: in vitro and in vivo characterization | journal = The Journal of Neuroscience | volume = 25 | issue = 17 | pages = 4396–405 | date = April 2005 | pmid = 15858066 | pmc = 6725110 | doi = 10.1523/JNEUROSCI.5269-04.2005 }}</ref> Also, there is evidence that indicates specific chaperone molecules have regulatory effects on these receptors.<ref name="pmid25771456">{{cite journal | vauthors = Sadigh-Eteghad S, Majdi A, Talebi M, Mahmoudi J, Babri S | title = Regulation of nicotinic acetylcholine receptors in Alzheimer׳s disease: a possible role of chaperones | journal = European Journal of Pharmacology | volume = 755 | pages = 34–41 | date = May 2015 | pmid = 25771456 | doi = 10.1016/j.ejphar.2015.02.047 | s2cid = 31929001 }}</ref>

==Roles== The subunits of the nicotinic receptors belong to a multigene family (16 members in humans) and the assembly of combinations of subunits results in a large number of different receptors (for more information see the [http://www.ebi.ac.uk/compneur-srv/LGICdb Ligand-Gated Ion Channel database]). These receptors, with highly variable kinetic, electrophysiological and pharmacological properties, respond to nicotine differently, at very different effective concentrations. This functional diversity allows them to take part in two major types of neurotransmission. Classical synaptic transmission (wiring transmission) involves the release of high concentrations of neurotransmitter, acting on immediately neighboring receptors. In contrast, paracrine transmission (volume transmission) involves neurotransmitters released by axon terminals, which then diffuse through the extra-cellular medium until they reach their receptors, which may be distant.<ref>{{cite journal | vauthors = Picciotto MR, Higley MJ, Mineur YS | title = Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior | journal = Neuron | volume = 76 | issue = 1 | pages = 116–29 | date = October 2012 | pmid = 23040810 | pmc = 3466476 | doi = 10.1016/j.neuron.2012.08.036 }}</ref> Nicotinic receptors can also be found in different synaptic locations; for example the muscle nicotinic receptor always functions post-synaptically. The neuronal forms of the receptor can be found both post-synaptically (involved in classical neurotransmission) and pre-synaptically<ref name="pmid9023878">{{cite journal | vauthors = Wonnacott S | title = Presynaptic nicotinic ACh receptors | journal = Trends in Neurosciences | volume = 20 | issue = 2 | pages = 92–8 | date = February 1997 | pmid = 9023878 | doi = 10.1016/S0166-2236(96)10073-4 | s2cid = 42215860 }}</ref> where they can influence the release of multiple neurotransmitters. Nicotine addiction arises from nAChR-mediated dopamine release in the mesolimbic pathway.

==Subunits== 17 vertebrate nAChR subunits have been identified, which are divided into muscle-type and neuronal-type subunits. Although an α₈ subunit/gene is present in avian species such as the chicken, it is not present in human or mammalian species.<ref name="pmid12150770">{{cite journal | vauthors = Graham A, Court JA, Martin-Ruiz CM, Jaros E, Perry R, Volsen SG, Bose S, Evans N, Ince P, Kuryatov A, Lindstrom J, Gotti C, Perry EK | display-authors = 6 | title = Immunohistochemical localization of nicotinic acetylcholine receptor subunits in human cerebellum | journal = Neuroscience | volume = 113 | issue = 3 | pages = 493–507 | year = 2002 | pmid = 12150770 | doi = 10.1016/S0306-4522(02)00223-3 | s2cid = 39839166 }}</ref>

The nAChR subunits have been divided into four subfamilies (I&ndash;IV) based on similarities in protein sequence.<ref name="pmid7699721">{{cite journal | vauthors = Le Novère N, Changeux JP | title = Molecular evolution of the nicotinic acetylcholine receptor: an example of multigene family in excitable cells | journal = Journal of Molecular Evolution | volume = 40 | issue = 2 | pages = 155–72 | date = February 1995 | pmid = 7699721 | doi = 10.1007/BF00167110 | bibcode = 1995JMolE..40..155L | s2cid = 2040912 }}</ref> In addition, subfamily III has been further divided into three types.

{| border="1" cellpadding="5" cellspacing="0" style="margin: 1em auto 1em auto;" |- | style="text-align: center; background:#66ccff;" colspan="5" | Neuronal-type | style="text-align: center; background:#ff6666;" | Muscle-type |- ! style="background:#99cccc;" width="100"| I ! style="background:#66cccc;" width="100"| II ! style="background:#33cccc;" width="300" colspan="3" | III ! style="background:#cc6666;" width="100"| IV |- | style="text-align: center;" rowspan="2"| α9, α10 | style="text-align: center;" rowspan="2"| α7, α8 | width="100" style="text-align: center; background:#99ffff;"| 1 | width="100" style="text-align: center; background:#66ffff;"| 2 | width="100" style="text-align: center; background:#33ffff;"| 3 | style="text-align: center;" rowspan="2"| α1, β1, δ, γ, ε |- | style="text-align: center;"| α2, α3, α4, α6 | style="text-align: center;"| β2, β4 | style="text-align: center;"| β3, α5 |}

* α genes: {{Gene|CHRNA1}} (muscle), {{Gene|CHRNA2}} (neuronal), {{Gene|CHRNA3}}, {{Gene|CHRNA4}}, {{Gene|CHRNA5}}, {{Gene|CHRNA6}}, {{Gene|CHRNA7}}, {{Gene|CHRNA8}}, {{Gene|CHRNA9}}, {{Gene|CHRNA10}} * β genes: {{Gene|CHRNB1}} (muscle), {{Gene|CHRNB2}} (neuronal), {{Gene|CHRNB3}}, {{Gene|CHRNB4}} * Other genes: {{Gene|CHRND}} (delta), {{Gene|CHRNE}} (epsilon), {{Gene|CHRNG}} (gamma)

Neuronal nAChRs are transmembrane proteins that form pentameric structures assembled from a family of subunits composed of α₂&ndash;α₁₀ and β₂&ndash;β₄.<ref name="Improgo et al 2010">{{cite journal | vauthors = Improgo MR, Scofield MD, Tapper AR, Gardner PD | title = The nicotinic acetylcholine receptor CHRNA5/A3/B4 gene cluster: dual role in nicotine addiction and lung cancer | journal = Progress in Neurobiology | volume = 92 | issue = 2 | pages = 212–26 | date = October 2010 | pmid = 20685379 | pmc = 2939268 | doi = 10.1016/j.pneurobio.2010.05.003 }}</ref> These subunits were discovered from the mid-1980s through the early 1990s, when cDNAs for multiple nAChR subunits were cloned from rat and chicken brains, leading to the identification of eleven different genes (twelve in chickens) that code for neuronal nAChR subunits; The subunit genes identified were named α₂&ndash;α₁₀ (α₈ only found in chickens) and β₂&ndash;β₄.<ref>{{cite journal | vauthors = Tammimäki A, Horton WJ, Stitzel JA | title = Recent advances in gene manipulation and nicotinic acetylcholine receptor biology | journal = Biochemical Pharmacology | volume = 82 | issue = 8 | pages = 808–19 | date = October 2011 | pmid = 21704022 | pmc = 3162071 | doi = 10.1016/j.bcp.2011.06.014 }}</ref> It has also been discovered that various subunit combinations could form functional nAChRs that could be activated by acetylcholine and nicotine, and the different combinations of subunits generate subtypes of nAChRs with diverse functional and pharmacological properties.<ref>{{cite journal | vauthors = Graham A, Court JA, Martin-Ruiz CM, Jaros E, Perry R, Volsen SG, Bose S, Evans N, Ince P, Kuryatov A, Lindstrom J, Gotti C, Perry EK | display-authors = 6 | title = Immunohistochemical localization of nicotinic acetylcholine receptor subunits in human cerebellum | journal = Neuroscience | volume = 113 | issue = 3 | pages = 493–507 | date = September 2002 | pmid = 12150770 | doi = 10.1016/S0306-4522(02)00223-3 | s2cid = 39839166 }}</ref> When expressed alone, α₇, α₈, α₉, and α₁₀ are able to form functional receptors, but other α subunits require the presence of β subunits to form functional receptors.<ref name="Improgo et al 2010"/> In mammals, nAchR subunits have been found to be encoded by 17 genes, and of these, nine genes encoding α-subunits and three encoding β-subunits are expressed in the brain. β₂ subunit-containing nAChRs (β₂nAChRs) and α₇nAChRs are widely expressed in the brain, whereas other nAChR subunits have more restricted expression.<ref>{{cite journal | vauthors = Changeux JP | title = Nicotine addiction and nicotinic receptors: lessons from genetically modified mice | journal = Nature Reviews. Neuroscience | volume = 11 | issue = 6 | pages = 389–401 | date = June 2010 | pmid = 20485364 | doi = 10.1038/nrn2849 | s2cid = 661315 }}</ref> The pentameric assembly of nAChRs is subjected to the subunits that are produced in various cell types such as in the human lung where epithelial and muscular pentamers largely differ.<ref>{{cite journal |last1=Diabasana |first1=Z |last2=Perotin |first2=JM |last3=Belgacemi |first3=R |last4=Ancel |first4=J |last5=Mulette |first5=P |last6=Delepine |first6=G |last7=Gosset |first7=P |last8=Maskos |first8=U |last9=Polette |first9=M |last10=Deslée |first10=G |last11=Dormoy |first11=V |title=Nicotinic Receptor Subunits Atlas in the Adult Human Lung |journal=Int. J. Mol. Sci. |date=2020 |volume=21 |issue=20 |page=7446 |doi=10.3390/ijms21207446 |pmid=33050277|pmc=7588933 |doi-access=free }}</ref>

===CHRNA5/A3/B4=== An important nAchR gene cluster (CHRNA5/A3/B4) contains the genes encoding for the α₅, α3 and β₄ subunits. Genetic studies have identified single nucleotide polymorphisms (SNPs) in the chromosomal locus encoding these three nAChR genes as risk factors for nicotine dependence, lung cancer, chronic obstructive pulmonary disease, alcoholism, and peripheral arterial disease.<ref name="Improgo et al 2010"/><ref name="Greenbaum & Lerer 2009"/> The CHRNA5/A3/B4 nAChR subunit genes are found in a tight cluster in chromosomal region 15q24–25. The nAChR subunits encoded by this locus form the predominant nicotinic receptor subtypes expressed in the peripheral nervous system (PNS) and other key central nervous system (CNS) sites, such as the medial habenula, a structure between the limbic forebrain and midbrain involved in major cholinergic circuitry pathways.<ref name="Improgo et al 2010"/> Further research of the CHRNA5/A3/B4 genes have revealed that "neuronal" nAChR genes are also expressed in non-neuronal cells where they are involved in various fundamental processes, such as inflammation.<ref>{{cite journal | vauthors = Gahring LC, Rogers SW | title = Neuronal nicotinic acetylcholine receptor expression and function on nonneuronal cells | journal = The AAPS Journal | volume = 7 | issue = 4 | pages = E885-94 | date = January 2006 | pmid = 16594641 | pmc = 2750958 | doi = 10.1208/aapsj070486 }}</ref> The CHRNA5/A3/B4 genes are co-expressed in many cell types and the transcriptional activities of the promoter regions of the three genes are regulated by many of the same transcription factors, demonstrating that their clustering may reflect control of gene expression.<ref name="Improgo et al 2010"/>

===CHRNA6/CHRNB3=== CHRNB3 and CHRNA6 are also grouped in a gene cluster, located on 8p11.<ref name="Greenbaum & Lerer 2009"/> Multiple studies have shown that SNPS in the CHRNB3–CHRNA6 have been linked to nicotine dependence and smoking behavior, such as two SNPs in CHRNB3, rs6474413 and rs10958726.<ref name="Greenbaum & Lerer 2009"/> Genetic variation in this region also displays influence susceptibility to use drugs of abuse, including cocaine and alcohol consumption.<ref name="Kamens et al 2016">{{cite journal | vauthors = Kamens HM, Corley RP, Richmond PA, Darlington TM, Dowell R, Hopfer CJ, Stallings MC, Hewitt JK, Brown SA, Ehringer MA | display-authors = 6 | title = Evidence for Association Between Low Frequency Variants in CHRNA6/CHRNB3 and Antisocial Drug Dependence | journal = Behavior Genetics | volume = 46 | issue = 5 | pages = 693–704 | date = September 2016 | pmid = 27085880 | pmc = 4975622 | doi = 10.1007/s10519-016-9792-4 }}</ref> Nicotinic receptors containing α₆ or β₃ subunits expressed in brain regions, especially in the ventral tegmental area and substantia nigra, are important for drug behaviors due to their role in dopamine release.<ref>{{cite journal | vauthors = Grady SR, Salminen O, Laverty DC, Whiteaker P, McIntosh JM, Collins AC, Marks MJ | title = The subtypes of nicotinic acetylcholine receptors on dopaminergic terminals of mouse striatum | journal = Biochemical Pharmacology | volume = 74 | issue = 8 | pages = 1235–46 | date = October 2007 | pmid = 17825262 | pmc = 2735219 | doi = 10.1016/j.bcp.2007.07.032 }}</ref> Genetic variation in these genes can alter sensitivity to drugs of abuse in numerous ways, including changing the amino acid structure of the protein or cause alterations in transcriptional and translational regulation.<ref name="Kamens et al 2016"/>

===CHRNA4/CHRNB2=== Other well studied nAChR genes include the CHRNA4 and CHRNB2, which have been associated as Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE) genes.<ref name="Greenbaum & Lerer 2009"/><ref name="Steinlein & Bertrand 2008">{{cite journal | vauthors = Steinlein OK, Bertrand D | title = Neuronal nicotinic acetylcholine receptors: from the genetic analysis to neurological diseases | journal = Biochemical Pharmacology | volume = 76 | issue = 10 | pages = 1175–83 | date = November 2008 | pmid = 18691557 | doi = 10.1016/j.bcp.2008.07.012 }}</ref> Both of these nAChR subunits are present in the brain and the occurrence of mutations in these two subunits cause a focal type of epilepsy. Examples include the CHRNA4 insertion mutation 776ins3 that is associated with nocturnal seizures and psychiatric disorders, and the CHRNB2 mutation I312M that seems to cause not only epilepsy but also very specific cognitive deficits, such as deficits in learning and memory.<ref name="Steinlein & Bertrand 2008"/><ref>{{cite journal | vauthors = Bertrand D, Elmslie F, Hughes E, Trounce J, Sander T, Bertrand S, Steinlein OK | title = The CHRNB2 mutation I312M is associated with epilepsy and distinct memory deficits | journal = Neurobiology of Disease | volume = 20 | issue = 3 | pages = 799–804 | date = December 2005 | pmid = 15964197 | doi = 10.1016/j.nbd.2005.05.013 | s2cid = 29811931 }}</ref> There is naturally occurring genetic variation between these two genes and analysis of single nucleotide polymorphisms (SNPs) and other gene modifications show a higher variation in the CHRNA4 gene than in the CHRNB2 gene, implying that nAChR β₂, the protein encoded by CHRNB2, associates with more subunits than α₄. CHRNA2 has also been reported as a third candidate for nocturnal frontal lobe seizures.<ref name="Greenbaum & Lerer 2009">{{cite journal | vauthors = Greenbaum L, Lerer B | title = Differential contribution of genetic variation in multiple brain nicotinic cholinergic receptors to nicotine dependence: recent progress and emerging open questions | journal = Molecular Psychiatry | volume = 14 | issue = 10 | pages = 912–45 | date = October 2009 | pmid = 19564872 | doi = 10.1038/mp.2009.59 | doi-access = free }}</ref><ref name="Steinlein & Bertrand 2008"/>

===CHRNA7=== Several studies have reported an association between CHRNA7 and endophenotypes of psychiatric disorders and nicotine dependence, contributing to the significant clinical relevance of α₇ and research being done on it.<ref name="Steinlein & Bertrand 2008"/> CHRNA7 was one of the first genes that had been considered to be involved with schizophrenia. Studies identified several CHRNA7 promoter polymorphisms that reduce the genes transcriptional activity to be associated with schizophrenia, which is consistent with the finding of reduced levels of a7 nAChRs in the brain of schizophrenic patients.<ref name="Steinlein & Bertrand 2008"/> Both nAChRs subtypes, α₄β₂ and α₇, have been found to be significantly reduced in post-mortem studies of individuals with schizophrenia.<ref>{{cite journal | vauthors = Breese CR, Lee MJ, Adams CE, Sullivan B, Logel J, Gillen KM, Marks MJ, Collins AC, Leonard S | display-authors = 6 | title = Abnormal regulation of high affinity nicotinic receptors in subjects with schizophrenia | journal = Neuropsychopharmacology | volume = 23 | issue = 4 | pages = 351–64 | date = October 2000 | pmid = 10989262 | doi = 10.1016/S0893-133X(00)00121-4 | doi-access = free }}</ref> Additionally, smoking rates are significantly higher in those with schizophrenia, implying that smoking nicotine may be a form of self-medicating.<ref>{{cite journal | vauthors = McLean SL, Grayson B, Idris NF, Lesage AS, Pemberton DJ, Mackie C, Neill JC | title = Activation of α7 nicotinic receptors improves phencyclidine-induced deficits in cognitive tasks in rats: implications for therapy of cognitive dysfunction in schizophrenia | journal = European Neuropsychopharmacology | volume = 21 | issue = 4 | pages = 333–43 | date = April 2011 | pmid = 20630711 | doi = 10.1016/j.euroneuro.2010.06.003 | hdl = 10454/8464 | s2cid = 41306366 | hdl-access = free }}</ref> CHRNA7 has also been shown to modulate immune responses though cholinergic anti-inflammatory pathway (CAP).<ref>{{Cite journal |last1=Báez-Pagán |first1=Carlos A. |last2=Delgado-Vélez |first2=Manuel |last3=Lasalde-Dominicci |first3=José A. |date=September 2015 |title=Activation of the Macrophage α7 Nicotinic Acetylcholine Receptor and Control of Inflammation |journal=Journal of Neuroimmune Pharmacology |volume=10 |issue=3 |pages=468–476 |doi=10.1007/s11481-015-9601-5 |issn=1557-1904 |pmc=4546521 |pmid=25870122}}</ref>

===Notable variations===<!--Ganglion type nicotinic receptor redirects here--> Nicotinic receptors are pentamers of these subunits; i.e., each receptor contains five subunits. Thus, there is immense potential of variation of these subunits, some of which are more commonly found than others. The most broadly expressed subtypes include (α₁)₂β₁δε (adult muscle-type), (α₃)₂(β₄)₃ (ganglion-type), (α₄)₂(β₂)₃ (CNS-type) and (α₇)₅ (another CNS-type).<ref name=Rang>{{cite book | vauthors = Rang HP | title = Pharmacology | edition = 5th | publisher = Churchill Livingstone | location = Edinburgh | year = 2003 | isbn = 978-0-443-07145-4 }}{{page needed|date=April 2020}}</ref> A comparison follows:

{| class="wikitable" |- ! Receptor-type !! Location !! Effect; functions !! Nicotinic agonists !! Nicotinic antagonists |- ! Muscle-type: <BR/> (α₁)₂β₁δε<ref name=Rang/> <BR/> or <BR/>(α₁)₂β₁δγ | Neuromuscular junction || EPSP, mainly by increased Na⁺ and K⁺ permeability || *acetylcholine<ref name="Purves" /> *carbachol *suxamethonium (succinylcholine) *decamethonium *pyrantel || *α-bungarotoxin<ref name=neurosci>[http://www.neurosci.pharm.utoledo.edu/MBC3320/nicotinic.htm Neurosci.pharm - MBC 3320 Acetylcholine] {{webarchive|url=https://web.archive.org/web/20071227192643/http://www.neurosci.pharm.utoledo.edu/MBC3320/nicotinic.htm |date=2007-12-27 }}</ref> *α-conotoxin *tubocurarine<ref name="Purves" /> *pancuronium *atracurium* |- ! Ganglion-type: <BR/> (α₃)₂(β₄)₃ | autonomic ganglia || EPSP, mainly by increased Na⁺ and K⁺ permeability || * acetylcholine<ref name="Purves" /> *carbachol *nicotine<ref name="Purves" /> *epibatidine *dimethylphenylpiperazinium

|| *bupropion *coniine *18-methoxycoronaridine *Dextromethorphan *hexamethonium *ibogaine *mecamylamine<ref name="Purves" /><ref name=neurosci/> *trimetaphan |- ! Heteromeric CNS-type: <BR/> (α₄)₂(β₂)₃ | Brain || Post- and presynaptic excitation,<ref name=Rang/> mainly by increased Na⁺ and K⁺ permeability. Major subtype involved in the attention-enhancing and rewarding effects of nicotine as well as the pathophysiology of nicotine addiction.<ref>{{cite journal | vauthors = Sarter M | title = Behavioral-Cognitive Targets for Cholinergic Enhancement | journal = Current Opinion in Behavioral Sciences | volume = 4 | pages = 22–26 | date = August 2015 | pmid = 28607947 | pmc = 5466806 | doi = 10.1016/j.cobeha.2015.01.004 }}</ref><ref>{{cite journal | vauthors = Wu J, Gao M, Shen JX, Shi WX, Oster AM, Gutkin BS | title = Cortical control of VTA function and influence on nicotine reward | journal = Biochemical Pharmacology | volume = 86 | issue = 8 | pages = 1173–80 | date = October 2013 | pmid = 23933294 | doi = 10.1016/j.bcp.2013.07.013 }}</ref><ref name="Nicotine IUPHAR">{{cite web|title=Nicotine: Biological activity|url=http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=biology&ligandId=2585|website=IUPHAR/BPS Guide to Pharmacology|publisher=International Union of Basic and Clinical Pharmacology|access-date=7 February 2016|quote=K_is as follows; α₂β₄=9900nM [5], α₃β₂=14nM [1], α₃β₄=187nM [1], α₄β₂=1nM [4,6]. Due to the heterogeneity of nACh channels we have not tagged a primary drug target for nicotine, although the α₄β₂ is reported to be the predominant high affinity subtype in the brain which mediates nicotine addiction [2-3].}}</ref>

|| *acetylcholine *cytisine *epibatidine *nicotine *nifene *varenicline || *α-conotoxin *Dextromethorphan *dihydro-β-erythroidine *mecamylamine *bupropion |- ! Further CNS-type: <BR/> (α₃)₂(β₄)₃<BR/> | Brain || Post- and presynaptic excitation || *acetylcholine *cytisine *epibatidine *nicotine || *Dextromethorphan *hexamethonium *mecamylamine *tubocurarine *bupropion |- ! Homomeric CNS-type: <BR/> (α₇)₅ <BR/> | Brain || Post- and presynaptic excitation,<ref name=Rang/> mainly by increased Na⁺, K⁺ and Ca²⁺ permeability. Major subtype involved in some of the cognitive effects of nicotine.<ref>{{cite journal | vauthors = Levin ED | title = α7-Nicotinic receptors and cognition | journal = Current Drug Targets | volume = 13 | issue = 5 | pages = 602–6 | date = May 2012 | pmid = 22300026 | doi = 10.2174/138945012800398937 }}</ref> Moreover, activation of (α₇)₅ could improve neurovascular coupling response in neurodegenerative disease<ref>{{cite journal | vauthors = Sadigh-Eteghad S, Mahmoudi J, Babri S, Talebi M | title = Effect of alpha-7 nicotinic acetylcholine receptor activation on beta-amyloid induced recognition memory impairment. Possible role of neurovascular function | journal = Acta Cirurgica Brasileira | volume = 30 | issue = 11 | pages = 736–42 | date = November 2015 | pmid = 26647792 | doi = 10.1590/S0102-865020150110000003 | doi-access = free }}</ref> and neurogenesis in ischemic stroke.<ref>{{cite journal | vauthors = Wang J, Lu Z, Fu X, Zhang D, Yu L, Li N, Gao Y, Liu X, Yin C, Ke J, Li L, Zhai M, Wu S, Fan J, Lv L, Liu J, Chen X, Yang Q, Wang J | display-authors = 6 | title = Alpha-7 Nicotinic Receptor Signaling Pathway Participates in the Neurogenesis Induced by ChAT-Positive Neurons in the Subventricular Zone | journal = Translational Stroke Research | volume = 8 | issue = 5 | pages = 484–493 | date = May 2017 | pmid = 28551702 | pmc = 5704989 | doi = 10.1007/s12975-017-0541-7 }}</ref> Also involved in the pro-angiogenic effects of nicotine and accelerate the progression of chronic kidney disease in smokers.<ref>{{cite journal | vauthors = Lee J, Cooke JP | title = Nicotine and pathological angiogenesis | journal = Life Sciences | volume = 91 | issue = 21–22 | pages = 1058–64 | date = November 2012 | pmid = 22796717 | pmc = 3695741 | doi = 10.1016/j.lfs.2012.06.032 }}</ref><ref>{{cite journal | vauthors = Jain G, Jaimes EA | title = Nicotine signaling and progression of chronic kidney disease in smokers | journal = Biochemical Pharmacology | volume = 86 | issue = 8 | pages = 1215–23 | date = October 2013 | pmid = 23892062 | pmc = 3838879 | doi = 10.1016/j.bcp.2013.07.014 }}</ref><ref name="pmid16766716">{{cite journal | vauthors = Mihalak KB, Carroll FI, Luetje CW | title = Varenicline is a partial agonist at alpha4beta2 and a full agonist at alpha7 neuronal nicotinic receptors | journal = Molecular Pharmacology | volume = 70 | issue = 3 | pages = 801–5 | date = September 2006 | pmid = 16766716 | doi = 10.1124/mol.106.025130 | s2cid = 14562170 }}</ref> || *acetylcholine *choline *nicotine *Cytisine *epibatidine *dimethylphenylpiperazinium *varenicline || *α-bungarotoxin<ref name="Purves" /> *amantadine *Dextromethorphan *mecamylamine *memantine *methylcaconitine |- |}

== See also == * Bupropion * Muscarinic agonist * Muscarinic antagonist * TDBzcholine * Myasthenia gravis * Congenital myasthenic syndrome * Adrenergic * Adrenergic receptor

== References == {{Reflist|30em}}

== External links == {{Wikiversity|Poisson–Boltzmann profile for an ion channel}} *{{Commons category-inline|Nicotinic acetylcholine receptors}} *[http://opm.phar.umich.edu/protein.php?pdbid=2bg9 Calculated spatial position of Nicotinic acetylcholine receptor in the lipid bilayer]

{{Autoantigens}} {{Ligand-gated ion channels}} {{Nicotinic acetylcholine receptor modulators}}

{{DEFAULTSORT:Nicotinic Acetylcholine Receptor}} Category:Nicotinic acetylcholine receptors Category:Ion channels Category:Autoantigens Category:Cell signaling Category:Acetylcholine receptors