Editing Acetylcholine receptor

{{Short description|Integral membrane protein}}
[[File:NAChR.png|thumb|300px| [[Nicotinic acetylcholine receptor]] structure]]
[[Image:Acetylcholine.svg|thumb|[[Acetylcholine]]]]

An '''acetylcholine receptor''' (abbreviated '''AChR''') or a '''cholinergic receptor''' is an [[integral membrane protein]] that responds to the binding of [[acetylcholine]], a [[neurotransmitter]].

==Classification==
Like other [[transmembrane receptor]]s, acetylcholine receptors are classified according to their "pharmacology," or according to their relative affinities and sensitivities to different molecules.  Although all acetylcholine receptors, by definition, respond to acetylcholine, they respond to other molecules as well.{{cn|date=April 2025}}
* [[Nicotinic acetylcholine receptor]]s (''nAChR'', also known  as "[[ionotropic receptor|ionotropic]]" acetylcholine receptors) are particularly responsive to [[nicotine]]. The nicotine ACh receptor is also a Na<sup>+</sup>, K<sup>+</sup> and Ca<sup>2+</sup> [[ion channel]].
* [[Muscarinic acetylcholine receptor]]s (''mAChR'', also known as "[[metabotropic receptor|metabotropic]]" acetylcholine receptors) are particularly responsive to [[muscarine]].

Nicotinic and muscarinic are two main kinds of "cholinergic" receptors.{{cn|date=April 2025}}

==Receptor types==
[[Molecular biology]] has shown that the nicotinic and muscarinic receptors belong to distinct [[protein superfamily|protein superfamilies]]. Nicotinic receptors are of two types: Nm and Nn. Nm<ref>{{cite web| url = http://image.slidesharecdn.com/anspharmacologyandcholinergics-drdhritiupdated2011-111228115516-phpapp02/95/autonomic-nervous-system-pharmacology-and-cholinergics-updated-2011-drdhriti-47-728.jpg?cb=1382965154| title = Reference at image.slidesharecdn.com}}</ref> is located in the neuromuscular junction which causes the contraction of skeletal muscles by way of [[end-plate potential]] (EPPs). Nn causes depolarization in autonomic ganglia resulting in post ganglionic impulse. Nicotinic receptors cause the release of catecholamine from the adrenal medulla, and also site specific excitation or inhibition in brain. Both Nm and Nn receptor types are non-selective cation channels, permeable to sodium and potassium ions, in addition to that, Nn type receptors allow for calcium ion flow.{{cn|date=April 2025}}

===nAChR===
{{Main|Nicotinic acetylcholine receptor}}
The nAChRs are [[ligand-gated ion channel]]s, and, like other members of the "[[cys-loop]]" ligand-gated ion channel superfamily, are composed of five [[protein subunit]]s symmetrically arranged like staves around a barrel. The subunit composition is highly variable across different tissues. Each subunit contains four regions which span the membrane and consist of approximately 20 amino acids.  Region II which sits closest to the pore lumen, forms the pore lining.{{cn|date=April 2025}}

Binding of acetylcholine to the N termini of each of the two alpha subunits results in the 15° rotation of all M2 helices.<ref name="pmid15165732">{{cite journal | author = Doyle DA | title = Structural changes during ion channel gating | journal = Trends Neurosci. | volume = 27 | issue = 6 | pages = 298–302 | year = 2004 | pmid = 15165732 | doi = 10.1016/j.tins.2004.04.004 | s2cid = 36451231 }}</ref> The cytoplasm side of the nAChR receptor has rings of high negative charge that determine the specific cation specificity of the receptor and remove the hydration shell often formed by ions in aqueous solution. In the intermediate region of the receptor, within the pore lumen, [[valine]] and [[leucine]] residues (Val 255 and Leu 251) define a hydrophobic region through which the dehydrated ion must pass.<ref name="pmid12827192">{{cite journal |vauthors=Miyazawa A, Fujiyoshi Y, Unwin N | title = Structure and gating mechanism of the acetylcholine receptor pore | journal = Nature | volume = 423 | issue = 6943 | pages = 949–55 | year = 2003 | pmid = 12827192 | doi = 10.1038/nature01748 | bibcode = 2003Natur.423..949M | s2cid = 205209809 }}</ref>

The nAChR is found at the [[Postsynaptic density|edges of junctional folds]] at the [[neuromuscular junction]] on the postsynaptic side; it is activated by [[acetylcholine]] release across the synapse. The diffusion of Na<sup>+</sup> and K<sup>+</sup> across the receptor causes depolarization, the end-plate potential, that opens [[voltage-gated sodium channel]]s, which allows for firing of the [[action potential]] and potentially muscular contraction.{{cn|date=April 2025}}

===mAChR===
{{Main|Muscarinic acetylcholine receptors}}
In contrast, the [[mAChRs]] are not ion channels, but belong instead to the superfamily of [[G-protein-coupled receptor]]s that activate other ionic channels via a [[second messenger]] cascade.
The muscarine cholinergic  receptor activates a G-protein when bound to extracellular ACh. The alpha subunit of the G-protein activates guanylate cyclase (inhibiting the effects of intracellular cAMP) while the beta-gamma subunit activates the K-channels and therefore hyperpolarize the cell. This causes a decrease in cardiac activity.{{cn|date=April 2025}}

== Origin and evolution ==
ACh receptors are related to [[Gamma-Aminobutyric acid|GABA]], [[Glycine receptor|glycine]], and [[5-HT3 receptor]]s and their similar protein sequence and gene structure strongly suggest that they evolved from a common ancestral receptor.<ref>{{Cite journal|last1=Ortells|first1=M. O.|last2=Lunt|first2=G. G.|date=March 1995|title=Evolutionary history of the ligand-gated ion-channel superfamily of receptors|url=https://pubmed.ncbi.nlm.nih.gov/7754520|journal=Trends in Neurosciences|volume=18|issue=3|pages=121–127|doi=10.1016/0166-2236(95)93887-4|issn=0166-2236|pmid=7754520|s2cid=18062185 }}</ref> In fact, relatively minor mutations, such as a change in 3 amino acids in many of these receptors can convert a cation-selective channel to an anion-selective channel gated by acetylcholine, showing that even fundamental properties can relatively easily change in evolution.<ref>{{Cite journal|last1=Galzi|first1=J. L.|last2=Devillers-Thiéry|first2=A.|last3=Hussy|first3=N.|last4=Bertrand|first4=S.|last5=Changeux|first5=J. P.|last6=Bertrand|first6=D.|date=1992-10-08|title=Mutations in the channel domain of a neuronal nicotinic receptor convert ion selectivity from cationic to anionic|url=https://pubmed.ncbi.nlm.nih.gov/1383829|journal=Nature|volume=359|issue=6395|pages=500–505|doi=10.1038/359500a0|issn=0028-0836|pmid=1383829|bibcode=1992Natur.359..500G |s2cid=4266961 }}</ref>

== Pharmacology ==
Acetylcholine receptor modulators can be classified by which receptor subtypes they act on:
{| class="wikitable"
|+ ACh and its receptors
! Drug !! [[Muscle-type nicotinic receptor|Nm]] !! [[Ganglion type nicotinic receptor|Nn]] !! [[Muscarinic acetylcholine receptor M1|M1]] !! [[Muscarinic acetylcholine receptor M2|M2]] !! [[Muscarinic acetylcholine receptor M3|M3]]
|-
| [[ACh]], [[Carbachol]], [[Methacholine]], [[AChEI]] ([[Physostigmine]], [[Galantamine]], [[Neostigmine]], [[Pyridostigmine]]) || + || + || + || + || +
|-
| [[Nicotine]], [[Varenicline]] || + || + || || ||
|-
| [[Succinylcholine]] || +/- || || || ||
|-
| [[Atracurium]], [[Vecuronium]], [[Tubocurarine]], [[Pancuronium]] || - || || || ||
|-
| [[Epibatidine]], [[DMPP]] || || + || || ||
|-
| [[Trimethaphan]], [[Mecamylamine]], [[Bupropion]], [[Dextromethorphan]], [[Hexamethonium]] || || - || || ||
|-
| [[Muscarine]], [[Oxotremorine]], [[Bethanechol]], [[Pilocarpine]] || || || + || + || +
|-
| [[Atropine]], [[Tolterodine]], [[Oxybutynin]] || || || - || - || -
|-
| [[Vedaclidine]], [[Talsaclidine]], [[Xanomeline]], [[Ipratropium]] || || || + || ||
|-
| [[Pirenzepine]], [[Telenzepine]] || || || - || ||
|-
| [[Methoctramine]] || || || || - ||
|-
| [[Darifenacin]], [[4-DAMP]], [[Solifenacin]] || || || || || -
|}

==Role in health and disease==
Nicotinic acetylcholine receptors can be blocked by [[curare]], [[hexamethonium]] and toxins present in the venoms of [[snake]]s and [[shellfish]]es, like [[alpha bungarotoxin|α-bungarotoxin]]. Drugs such as the [[neuromuscular blocking agent]]s bind reversibly to the nicotinic receptors in the [[neuromuscular junction]] and are used routinely in anaesthesia. Nicotinic receptors are the primary mediator of the effects of [[nicotine]]. In [[myasthenia gravis]], the receptor at the neuromuscular junction is targeted by [[antibody|antibodies]], leading to muscle weakness.{{cn|date=April 2025}}

Muscarinic acetylcholine receptors can be blocked by the drugs [[atropine]] and [[Hyoscine hydrobromide|scopolamine]].{{cn|date=April 2025}}

[[Congenital myasthenic syndrome]] (CMS) is an inherited neuromuscular disorder caused by defects of several types at the [[neuromuscular junction]]. Postsynaptic defects are the most frequent cause of CMS and often result in abnormalities in nicotinic acetylcholine receptors. The majority of mutations causing CMS are found in the AChR subunits genes.<ref name="Cossins">{{Cite journal
| last1 = Cossins | first1 = J.
| last2 = Burke | first2 = G.
| last3 = Maxwell | first3 = S.
| last4 = Spearman | first4 = H.
| last5 = Man | first5 = S.
| last6 = Kuks | first6 = J.
| last7 = Vincent | first7 = A.
| last8 = Palace | first8 = J.
| last9 = Fuhrer | first9 = C.
| last10 = Beeson | first10 = D.
| title = Diverse molecular mechanisms involved in AChR deficiency due to rapsyn mutations
| doi = 10.1093/brain/awl219
| journal = Brain
| volume = 129
| issue = 10
| pages = 2773–2783
| year = 2006
| pmid = 16945936
| doi-access = free
}}</ref>

Out of all mutations associated with CMS, more than half are mutations in one of the four genes encoding the adult acetylcholine receptor subunits. Mutations of the AChR often result in endplate deficiency. Most of the mutations of the AChR are mutations of the [[CHRNE]] gene with mutations encoding for the [[Alpha5 Nicotinic Acetylcholine Receptor]] cause increased susceptibility to addiction. The CHRNE gene codes for the epsilon subunit of the AChR. Most mutations are autosomal recessive loss-of-function mutations and as a result there is endplate AChR deficiency. CHRNE is associated with changing the kinetic properties of the AChR.<ref>{{Cite journal
| last1 = Abicht | first1 = A.
| last2 = Dusl | first2 = M.
| last3 = Gallenmüller | first3 = C.
| last4 = Guergueltcheva | first4 = V.
| last5 = Schara | first5 = U.
| last6 = Della Marina | first6 = A.
| last7 = Wibbeler | first7 = E.
| last8 = Almaras | first8 = S.
| last9 = Mihaylova | first9 = V.
| last10 = Von Der Hagen
| doi = 10.1002/humu.22130 | first10 = M.
| last11 = Huebner | first11 = A.
| last12 = Chaouch | first12 = A.
| last13 = Müller | first13 = J. S.
| last14 = Lochmüller | first14 = H.
| title = Congenital myasthenic syndromes: Achievements and limitations of phenotype-guided gene-after-gene sequencing in diagnostic practice: A study of 680 patients
| journal = Human Mutation
| volume = 33
| issue = 10
| pages = 1474–1484
| year = 2012
| pmid = 22678886
| s2cid = 30868022
}}</ref> One type of mutation of the epsilon subunit of the AChR introduces an Arg into the binding site at the α/ε subunit interface of the receptor. The addition of a cationic Arg into the anionic environment of the AChR binding site greatly reduces the kinetic properties of the receptor. The result of the newly introduced ARG is a 30-fold reduction of agonist affinity, 75-fold reduction of gating efficiency, and an extremely weakened channel opening probability. This type of mutation results in an extremely fatal form of CMS.<ref>{{Cite journal
| last1 = Shen | first1 = X. -M.
| last2 = Brengman | first2 = J. M.
| last3 = Edvardson | first3 = S.
| last4 = Sine | first4 = S. M.
| last5 = Engel | first5 = A. G.
| title = Highly fatal fast-channel syndrome caused by AChR subunit mutation at the agonist binding site
| doi = 10.1212/WNL.0b013e31825b5bda
| journal = Neurology
| volume = 79
| issue = 5
| pages = 449–454
| year = 2012
| pmid = 22592360
| pmc =3405251
}}</ref>

==See also==
* [[Nicotinic agonist]]
* [[Nicotinic acetylcholine receptor]]
* [[Muscarinic acetylcholine receptor]]
:* [[Muscarinic acetylcholine receptor M5]]
* [[Adrenergic receptor]]

== References ==
{{Reflist|28em}}

==External links==
{{Commons category}}
* [https://www.youtube.com/watch?v=4m_PMJB5hlM Acetylcholine receptor]: PMAP [[The Proteolysis Map]]-animation
* {{MeshName|Acetylcholine+Receptors}}
* [http://www.rcsb.org/pdb/101/motm.do?momID=71 Acetylcholine Receptor]: Molecule of The Month by David Goodsell
* [http://pharmacologycorner.com/acetylcholine-receptors-muscarinic-and-nicotinic/ Acetylcholine receptors: muscarinic and nicotinic] by Flavio Guzman
* [https://web.archive.org/web/20131204011631/http://www.aspet.org/uploadedFiles/Divisions_and_Chapters/ASPET_Divisions/Neuropharmacology/Content/ans-receptors-overview.ppt ANS receptors-overview]

{{Ligand-gated ion channels}}
{{G protein-coupled receptors}}
{{Acetylcholine receptor modulators}}

[[Category:Acetylcholine receptors| ]]