Muscarinic acetylcholine receptor: Difference between revisions

'''Muscarinic acetylcholine receptors''', or '''mAChRs''', are [[acetylcholine receptor]]s that form [[G protein-coupled receptor|G protein-coupled receptor complexes]] in the [[cell membrane]]s of certain [[neurons]]<ref name="pmid16879488">{{cite journal | vauthors = Eglen RM | title = Muscarinic receptor subtypes in neuronal and non-neuronal cholinergic function | journal = Autonomic & Autacoid Pharmacology | volume = 26 | issue = 3 | pages = 219–33 | date = July 2006 | pmid = 16879488 | doi = 10.1111/j.1474-8673.2006.00368.x }}</ref> and other [[Cell (biology)|cell]]s. They play several roles, including acting as the main end-receptor stimulated by [[acetylcholine]] released from [[postganglionic fibers]]. They are mainly found in the [[parasympathetic nervous system]], but also have a role in the [[sympathetic nervous system]] in the control of [[Sweat gland|sweat glands]].<ref>{{Citation |last=Kudlak |first=Megan |title=Physiology, Muscarinic Receptor |date=2024 |work=StatPearls |url=http://www.ncbi.nlm.nih.gov/books/NBK555909/ |access-date=2024-06-07 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=32310369 |last2=Tadi |first2=Prasanna}}</ref>

Muscarinic receptors are so named because they are more sensitive to [[muscarine]] than to [[nicotine]].<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 | year = 2006 | pmid = 17073660 | doi = 10.2174/138161206778522056 | url = http://www.bentham-direct.org/pages/content.php?CPD/2006/00000012/00000028/0002B.SGM | access-date = 2020-04-10 | url-status = dead | archive-url = https://web.archive.org/web/20090205000211/http://www.bentham-direct.org/pages/content.php?CPD%2F2006%2F00000012%2F00000028%2F0002B.SGM | archive-date = 2009-02-05 }}</ref> Their counterparts are [[nicotinic acetylcholine receptor]]s (nAChRs), receptor ion channels that are also important in the [[autonomic nervous system]]. Many drugs and other substances (for example [[pilocarpine]] and [[Hyoscine hydrobromide|scopolamine]]) manipulate these two distinct receptors by acting as selective [[agonist]]s or [[receptor antagonist|antagonist]]s.<ref name="Purves" >{{cite book | author = Purves, Dale, George J. Augustine, David Fitzpatrick, William C. Hall, Anthony-Samuel LaMantia, James O. McNamara, and Leonard E. White | title = Neuroscience. 4th ed. | publisher = Sinauer Associates | pages = 122–6 | year = 2008 | isbn = 978-0-87893-697-7}}</ref>

[[acetylcholine|ACh]] is always used as the [[neurotransmitter]] within the [[autonomic ganglion]]. Nicotinic receptors on the postganglionic neuron are responsible for the initial fast depolarization (Fast [[Excitatory postsynaptic potential|EPSP]]) of that neuron. As a consequence of this, nicotinic receptors are often cited as ''the receptor on the postganglionic neurons at the ganglion''. However, the subsequent hyperpolarization ([[IPSP]]) and slow depolarization (Slow EPSP) that represent the recovery of the postganglionic neuron from stimulation are actually mediated by ''muscarinic'' receptors, types M₂ and M₁ respectively (discussed below).{{citation needed|date=October 2014}}

Muscarinic acetylcholine receptors belong to a class of [[metabotropic receptor]]s that use [[G protein]]s as their signaling mechanism. In such receptors, the signaling molecule (the [[ligand]]) binds to a monomeric [[receptor (biochemistry)|receptor]] that has [[seven transmembrane region]]s; in this case, the ligand is ACh. This receptor is bound to intracellular proteins, known as G proteins, which begin the information cascade within the cell.<ref name="Kou Qin"/>

By contrast, nicotinic receptors form pentameric complexes and use a [[ligand-gated ion channel]] mechanism for signaling. In this case, binding of the ligands with the receptor causes an [[ion channel]] to open, permitting either one or more specific type(s)types of ionions (e.g., K⁺, Na⁺, Ca²⁺) to diffuse into or out of the cell.

By the use of selective radioactively labeled agonist and antagonist substances, five subtypes of muscarinic receptors have been determined, named M₁-M–M₅ (using an upper case M and subscript number).<ref name="pmid9647869">{{cite journal | vauthors = Caulfield MP, Birdsall NJ | title = International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors | journal = Pharmacological Reviews | volume = 50 | issue = 2 | pages = 279–90 | date = June 1998 | pmid = 9647869 | url = http://pharmrev.aspetjournals.org/content/50/2/279.short }}</ref> [[Muscarinic acetylcholine receptor M1|M₁]], [[Muscarinic acetylcholine receptor M3|M₃]], [[Muscarinic acetylcholine receptor M5|M₅]] receptors are coupled with [[Gq alpha subunit|G_q proteins]], while [[Muscarinic acetylcholine receptor M2|M₂]] and [[Muscarinic acetylcholine receptor M4|M₄]] receptors are coupled with G_i/o proteins.<ref name="Kou Qin">{{cite journal | vauthors = Qin K, Dong C, Wu G, Lambert NA | title = Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers | journal = Nature Chemical Biology | volume = 7 | issue = 10 | pages = 740–7 | date = August 2011 | pmid = 21873996 | pmc = 3177959 | doi = 10.1038/nchembio.642 }}</ref> There are other classification systems. For example, the drug [[pirenzepine]] is a muscarinic antagonist (decreases the effect of ACh), which is much more potent at M₁ receptors than it is at other subtypes. The acceptance of the various subtypes has proceeded in numerical order:, therefore, earlier sources thatmay recognize only the M₁/ and M₂ distinction exist.subtypes,{{Citation needed|date=December 2016}} while More recentlater studies tend to recognize M₃ and the most recent, M₄.,[http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=2] and most recently M₅ subtypes.{{Citation needed|date=DecemberNovember 20162021}}

Meanwhile, [[geneticist]]s and [[molecular biologist]]s have characterised five genes that appear to encode muscarinic receptors, named m1-m5 (lowercase m; no subscript number). The first fourThey code for pharmacologic types M₁-M₄. The fifth, M₅, corresponds to a subtype of receptor that had until recently not been detected pharmacologically. The receptors m1 and m2 were determined based upon partial sequencing of M₁ and M₂ receptor proteins. The others were found by searching for homology, using [[bioinformatic]] techniques.

G proteins contain an alpha-subunit that is critical to the functioning of receptors. These subunits can take a number of forms. There are four broad classes of form of G-protein: G_s, G_i, G_q, and G_12/13.<ref name="pmid1902986">{{cite journal | vauthors = Simon MI, Strathmann MP, Gautam N | title = Diversity of G proteins in signal transduction | journal = Science | volume = 252 | issue = 5007 | pages = 802–8 | date = May 1991 | pmid = 1902986 | doi = 10.1126/science.1902986 | bibcode = 1991Sci...252..802S | s2cid = 19110329 }}</ref> Muscarinic receptors vary in the G protein to which they are bound, with some correlation according to receptor type. G proteins are also classified according to their susceptibility to [[cholera toxin]] (CTX) and [[pertussis toxin]] (PTX, whooping cough). G_s and some subtypes of G_i (G_αt and G_αg) are susceptible to CTX. Only G_i is susceptible to PTX, with the exception of one subtype of G_i (G_αz) which is immune. Also, only when bound with an agonist, those G proteins normally sensitive to PTX also become susceptible to CTX.<ref name="pmid8449930">{{cite journal | vauthors = Dell'Acqua ML, Carroll RC, Peralta EG | title = Transfected m2 muscarinic acetylcholine receptors couple to G alpha i2 and G alpha i3 in Chinese hamster ovary cells. Activation and desensitization of the phospholipase C signaling pathway | journal = The Journal of Biological Chemistry | volume = 268 | issue = 8 | pages = 5676–85 | date = March 1993 | doi = 10.1016/S0021-9258(18)53372-X | pmid = 8449930 | url = http://www.jbc.org/cgi/content/abstract/268/8/5676 | doi-access = free }}</ref>

!Agonists<ref name="Tripathi_2004">{{cite book | author = Tripathi KD | title = Essentials of Medical Pharmacology | publisher = Jaypee Brothers, Medical Publishers | location = India | year = 2004 | edition = 5th | pages = 890 pages | isbn = 978-81-8061-187-2 | oclc = }} if nothing else mentioned in table</ref>

|-

| '''[[Muscarinic acetylcholine receptor M1|M₁]]''' || {{Gene|CHRM1}}||

* [[excitatory postsynaptic potential|EPSP]] in [[autonomic ganglia]]

|| no <BRbr> (yes) || no <BRbr> (yes) || [[Gq alpha subunit|G_q]] <BRbr> ([[Gi alpha subunit|G_i]]) <BRbr> ([[Gs alpha subunit|G_s]]): <BRbr> Slow [[Excitatory postsynaptic potential|EPSP]]. <BRbr> ↓ [[potassium|K⁺]] conductance<ref name=Rang/><ref name="pmid1693682">{{cite journal | vauthors = Uchimura N, North RA | title = Muscarine reduces inwardly rectifying potassium conductance in rat nucleus accumbens neurones | journal = The Journal of Physiology | volume = 422 | issue = 1 | pages = 369–80 | date = March 1990 | pmid = 1693682 | pmc = 1190137 | doi = 10.1113/jphysiol.1990.sp017989 | url = http://jp.physoc.org/cgi/content/abstract/422/1/369 | access-date = 2008-02-25 | url-status = dead | archive-url = https://web.archive.org/web/20090130030805/http://jp.physoc.org/cgi/content/abstract/422/1/369 | archive-date = 2009-01-30 }}</ref>||

* [[acetylcholine]]

* [[muscarineoxotremorine]]

* [[Hyoscine hydrobromide|scopolamine]]<ref name=Rang/>

* [[Diphenhydramine]]

* [[Dimenhydrinate]]

* [[tolterodinedicycloverine]]<ref name=Rang/>

* [[oxybutynintolterodine]]<ref name=Rang/>

* [[ipratropiumoxybutynin]]<ref name=Rang/>

* [[ipratropium]]<ref name=Rang/>
* [[mamba toxin]] [[Muscarinic toxin 7|MT7]]<ref name=Rang/>

* [[mamba toxin]] [[Muscarinic toxin 1|MT1]]<ref name=Servent>

* [[mamba toxin]] [[Muscarinic toxin 2|MT2]]<ref name="Karlsson">{{cite journal | vauthors = Karlsson E, Jolkkonen M, Mulugeta E, Onali P, Adem A | title = Snake toxins with high selectivity for subtypes of muscarinic acetylcholine receptors | journal = Biochimie | volume = 82 | issue = 9–10 | pages = 793–806 | date = September 2000 | pmid = 11086210 | doi = 10.1016/S0300-9084(00)01176-7 }}</ref>

* [[pirenzepine]]

* [[telenzepine]]

* [[chlorpromazine]]

* [[haloperidol]]

|-

* slow [[heart rate]]

* reduce [[inotrope|contractile forces]] of [[heart atrium|atrium]]

* reduce [[chronotropic|conduction velocity]] of [[atrioventricular node|AV node]]

* In [[central nervous system|CNS]]

* [[homotropic inhibition]]

|| yes || no || [[Gi alpha subunit|G_i]] <BRbr> ↑ [[potassium|K⁺]] conductance<ref name=Rang/> <BRbr> ↓ [[calcium|Ca²⁺]] conductance<ref name=Rang/> ||

* [[acetylcholine]]

* [[methacholine]]
* [[carbachol]]<ref name=Rang/>

* [[oxotremorine]]<ref name=Rang/>

* [[muscarine]]

||

* [[atropineHyoscine hydrobromide|scopolamine]]<ref name=Rang/>

* [[hyoscyamineatropine]]<ref name=nhl-hyoRang/>

* [[dicycloverinehyoscyamine]]<ref name=Rangnhl-hyo/>

* [[Diphenhydramine]]

* [[Dimenhydrinate]]

* [[tolterodine]]<ref name=Rang/>

* [[oxybutynin]]<ref name=Rang/>

* [[ipratropium]]<ref name=Rang/>

* induce [[bethanecholemesis]]

* [[oxotremorineacetylcholine]]<ref name=Rang"Kou Qin"/>

* [[atropinecarbachol]]<ref name="Kou Qin"/><ref name=Rang/>

* [[hyoscyamineoxotremorine]]<ref name=nhl-hyoRang/>

* [[dicycloverineHyoscine hydrobromide|scopolamine]]<ref name=Rang/>

* [[tolterodineatropine]]<ref name="Kou Qin"/><ref name=Rang/>

* [[oxybutyninhyoscyamine]]<ref name=Rangnhl-hyo/>

* [[darifenacinDimenhydrinate]]

* In [[central nervous system|CNS]]

|| yes || ? || [[Gi alpha subunit|G_i]] <BRbr> ↑ [[potassium|K⁺]] conductance<ref name=Rang/> <BRbr> ↓ [[calcium|Ca²⁺]] conductance<ref name=Rang/> ||

* [[acetylcholine]]

* [[carbacholarecoline]]<ref name=Rang"arecoline_receptors"/>

* [[oxotremorinecarbachol]]<ref name=Rang/>

*[[mamba toxin]] [[Muscarinic toxin 2|MT2dicycloverine]]<ref name="Karlsson"Rang/>

* [[mamba toxintolterodine]] MT3<ref name=Rang/>

* [[Diphenhydramineacetylcholine]]

* [[dicycloverineoxotremorine]]<ref name=Rang/>

* [[oxybutyninatropine]]<ref name=Rang/>

This receptor is found mediating slow [[excitatory postsynaptic potential|EPSP]] at the ganglion in the postganglionic nerve{{citation needed|date=October 2014}}, is common in [[exocrine gland]]s and in the CNS.<ref name="isbn1-55009-109-3">{{cite book | author = Johnson, Gordon | title = PDQ Pharmacology | publisher = BC Decker Inc | location = Hamilton, Ontario | year = 2002 | edition = 2nd | pages = 311 pages | isbn = 978-1-55009-109-0 | oclc = | doi = }}</ref><ref name="Richelson_2000">{{cite web |url= http://www.acnp.org/g4/GN401000011/Default.htm |title= Cholinergic Transduction, Psychopharmacology - The Fourth Generation of Progress |access-date=2007-10-27 |author = Richelson, Elliott | year= 2000 |publisher= American College of Neuropsychopharmacology }}</ref>

It is predominantly found bound to G proteins of class [[Gq alpha subunit|G_q]],<ref name="pmid8645172">{{cite journal | vauthors = Burford NT, Nahorski SR | title = Muscarinic m1 receptor-stimulated adenylate cyclase activity in Chinese hamster ovary cells is mediated by Gs alpha and is not a consequence of phosphoinositidase C activation | journal = The Biochemical Journal | volume = 315 ( Pt 3) | issue = 3 | pages = 883–8 | date = May 1996 | pmid = 8645172 | pmc = 1217289 | urldoi = http://www10.biochemj.org/bj/3151042/bj3150883.htm }}</ref> which use upregulation of [[phospholipase]] C and, therefore, [[inositol trisphosphate]] and intracellular calcium as a signaling pathway. A receptor so bound would not be susceptible to CTX or PTX. However, G_i (causing a downstream decrease in [[cyclic adenosine monophosphate|cAMP]]) and G_s (causing an increase in cAMP) have also been shown to be involved in interactions in certain tissues, and so would be susceptible to PTX and CTX, respectively.

The M₂ muscarinic receptors are located in the heart, whereand lungs. In the heart, they act to slow the [[heart rate]] down below the normal baseline [[sinus rhythm]], by slowing the speed of [[depolarization]]. In humans, under resting conditions, vagal activity dominates over sympathetic activity. Hence, inhibition of m2M₂ receptors (e.g. by atropine) will cause a raise in heart rate. They also moderately reduce contractile forces of the [[heart atrium|atrial]] [[cardiac muscle]], and reduce conduction velocity of the [[atrioventricular node]] (AV node). It also serves to slightly decrease the contractile forces of the [[heart ventricle|ventricular]] muscle.

The M₃ muscarinic receptors are located at many places in the body. They are located in the smooth muscles of the blood vessels, as well as in the lungs. Because the M₃ receptor is G_q-coupled and mediates an increase in intracellular calcium, it typically causes contraction of smooth muscle, such as that observed during [[bronchoconstriction]] and [[urinary incontinence|bladder voiding]].<ref name="Moro et al. 2011">{{cite journal | vauthors = Moro C, Uchiyama J, Chess-Williams R | title = Urothelial/lamina propria spontaneous activity and the role of M3 muscarinic receptors in mediating rate responses to stretch and carbachol | journal = Urology | volume = 78 | issue = 6 | pages = 1442.e9–15 | date = December 2011 | pmid = 22001099 | doi = 10.1016/j.urology.2011.08.039 }}</ref> However, with respect to vasculature, activation of M₃ on vascular endothelial cells causes increased synthesis of [[nitric oxide]], [[vasodilation|which diffuses to adjacent vascular smooth muscle cells and causes their relaxation]], thereby explaining the paradoxical effect of [[parasympathomimetic]]s on vascular tone and bronchiolar tone. Indeed, direct stimulation of vascular smooth muscle, M₃ mediates vasconstrictionvasoconstriction in pathologiesdiseases wherein the vascular endothelium is disrupted.<ref name="isbn0-07-142280-3">{{cite book |author1=Keith Parker |author2=Laurence Brunton |author3=Goodman, Louis Sanford |author4=Lazo, John S. |author5=Gilman, Alfred | title = Goodman & Gilman's the pharmacological basis of therapeutics |url=https://archive.org/details/goodmangilmansph00brun_116 |url-access=limited | publisher = McGraw-Hill | location = New York | edition = 11th | year = 2006 | pages = [https://archive.org/details/goodmangilmansph00brun_116/page/n210 185] | isbn = 978-0-07-142280-2 | oclc = }}</ref>

Like the M₁ and M₃ muscarinic receptor, M₅ receptors are coupled with G proteins of class [[Gq alpha subunit|G_q]] that upregulate phospholipase C and, therefore, inositol trisphosphate and intracellular calcium as a signaling pathway.{{citation needed|date=July 2022}}

[[ligand (biochemistry)|Ligands]] targeting the mAChR that are currently approved for clinical use include non-selective antagonists for the treatment of [[Parkinson's disease]],<ref name="pmid18082893">{{cite journal | vauthors = Langmead CJ, Watson J, Reavill C | title = Muscarinic acetylcholine receptors as CNS drug targets | journal = Pharmacology & Therapeutics | volume = 117 | issue = 2 | pages = 232–43 | date = February 2008 | pmid = 18082893 | doi = 10.1016/j.pharmthera.2007.09.009 }}</ref> [[atropine]] (to dilate the [[pupil]]), [[Hyoscine hydrobromide|scopolamine]] (used to prevent [[motion sickness]]), and [[ipratropium]] (used in the treatment of [[COPD]]).<ref name="Purves" /><ref>{{Citecite journal |last vauthors = Matera|first=Carlo|last2= C, Tata AM |first2=Ada| title = Pharmacological Approachesapproaches to Targetingtargeting Muscarinicmuscarinic Acetylcholineacetylcholine receptors Receptors| journal = Recent Patents on CNS Drug Discovery |language=en| volume = 9 | issue = 2 | pages = 85–100 |doi year =10.2174/1574889809666141120131238 2014 | pmid = 25413004 |year doi =2014 10.2174/1574889809666141120131238 }}</ref>

* [[Nicotinic acetylcholineAcetylcholine receptor]] (Cholinergic receptor)

* {{cite web | url = [http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1271 | title = Acetylcholine Receptors (Muscarinic) | access-date = | format = | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | pages = | archive-url = | archive-date = | quote = }}]