Muscarinic acetylcholine receptor 743435 224090160 2008-07-07T07:07:26Z DOI bot 6652755 Citation maintenance. Removed redundant parameters. Initiated by [[User:Boghog2|Boghog2]]. You can [[WP:DOI|use this bot]] yourself! Please [[User:DOI_bot/bugs|report any bugs]]. [[Image:Amanita muscaria 2.jpg|right|thumb|''[[Amanita muscaria]]'' from which muscarine was isolated]] [[Image:ACh.png|thumb|[[Acetylcholine]] - natural agonist of muscarinic and [[nicotinic acetylcholine receptor|nicotinic]] receptors.]] [[Image:Muscarine structure.png|thumb|[[Muscarine]] - agonist used to distinguish between these two classes of receptors. Not normally found in the body.]] [[Image:Atropine.svg|thumb|180px|[[Atropine]] - antagonist.]] '''Muscarinic receptors''' (mAChRs) are those membrane-bound [[acetylcholine receptor]]s that are more sensitive to [[muscarine]] than to [[nicotine]].<ref name="pmid17073660">{{cite journal | author = Ishii M, Kurachi Y | title = Muscarinic acetylcholine receptors | journal = Curr. Pharm. Des. | volume = 12 | issue = 28 | pages = 3573–81 | year = 2006 | pmid = 17073660 | doi = | url = http://www.bentham-direct.org/pages/content.php?CPD/2006/00000012/00000028/0002B.SGM}}</ref> Those for which the contrary is true are known as [[nicotinic acetylcholine receptor]]s (nAChRs). Muscarine and nicotine are both [[alkaloid]]s. Many drugs and other substances (for example [[pilocarpine]] and [[scopolamine]]) act as [[agonist]]s or [[receptor antagonist|antagonist]]s of only muscarinic or only nicotinic receptors, making this distinction useful. The mAChRs are a type of [[G protein-coupled receptor]] which together with the nAchRs, mediate the actions of acetylcholine in the nervous system.<ref name="pmid16879488">{{cite journal | author = Eglen RM | title = Muscarinic receptor subtypes in neuronal and non-neuronal cholinergic function | journal = Auton Autacoid Pharmacol | volume = 26 | issue = 3 | pages = 219–33 | year = 2006 | month = July | pmid = 16879488 | doi = 10.1111/j.1474-8673.2006.00368.x | url = }}</ref> ==Pharmacological application== The only [[ligand (biochemistry)|ligands]] targeting the mAChR currently approved for use in the clinic are non-selective antagonists for the treatment of [[Parkinson's disease]].<ref name="pmid18082893">{{cite journal | author = Langmead CJ, Watson J, Reavill C | title = Muscarinic acetylcholine receptors as CNS drug targets | journal = Pharmacol. Ther. | volume = 117 | issue = 2 | pages = 232–43 | year = 2008 | month = February | pmid = 18082893 | doi = 10.1016/j.pharmthera.2007.09.009 | url = }}</ref> ==Function== Acetylcholine (ACh) is a [[neurotransmitter]] found extensively in the [[brain]] and autonomic nervous system. It is also the neurotransmitter used to cause voluntary muscle contraction. Muscarinic receptors are used in the following roles: ===Sympathetic and parasympathetic postganglionic: recovery receptors === ACh is always used as the transmitter within the [[autonomic ganglion]]. Nicotinic receptors on the postganglionic neuron are responsible for the initial fast depolarization (Fast [[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) which represent the recovery of the postganglionic neuron from stimulation are actually mediated by ''muscarinic'' receptors, types M<sub>2</sub> and M<sub>1</sub> respectively (discussed later). ===Presynaptically within the postganglionic neurons=== Another role for these receptors is at the junction of the innervated tissue and the postganglionic neuron in the parasympathetic division of the autonomic nervous system. Here acetylcholine is again used as a neurotransmitter, and ''muscarinic'' receptors form the principal receptors on the innervated tissue. In addition, muscarinic acetylcholine receptors pre-synaptically on the post-ganglionic neuron bind to the released acetylcholine and regulate the response of the postganglionic neuron. ===Between the postganglionic neurons and the innervated tissue=== By contrast, this junction in the sympathetic division does not tend to use acetylcholine as a neurotransmitter (instead, norepinephrine is used), and therefore neither muscarinic nor nicotinic receptors are involved, but rather [[adrenergic receptor|adrenergic]] [[alpha-1 adrenergic receptor|α<sub>1</sub>]] and [[beta-1 adrenergic receptor|β<sub>1</sub>]] receptors. A very few parts of the sympathetic system use cholinergic receptors (sweat glands being one of the few exceptions). In these cases, the receptors are of the ''muscarinic'' type. The sympathetic nervous system also has single nerves terminating at the [[chromaffin cell]]s in the [[adrenal medulla]], which secrete [[epinephrine]] and [[norepinephrine]] into the bloodstream. Acetylcholine is used as a neurotransmitter, and the receptor is of the ''nicotinic'' type. The somatic nervous system uses acetylcholine at the junction between its one peripheral nerve and the innervated tissue, also of the nicotinic type. ===In the higher central nervous system=== Muscarinic acetylcholine receptors are also present and distributed throughout the central nervous system, in post-synaptic and pre-synaptic positions. There is also some evidence for [[postsynaptic]] receptors on sympathetic neurons allowing the parasympathetic nervous system to inhibit sympathetic effects. ===On the presynaptic membrane of the neuromuscular junction=== It's now known they also appear on the pre-synaptic membrane of somatic neurons in the neuro-muscular junction, where they are involved in the regulation of acetylcholine release. ==The form of muscarinic receptors== Muscarinic acetylcholine receptors belong to a class of [[metabotropic receptor]]s which use [[G protein]]s as their signalling mechanism. There are known to be a large number of these [[G-protein-coupled receptor]]s for [[neurotransmitter]]s, [[hormone]]s, and other substances. G proteins are also present in taste, and odour detecting [[cell (biology)|cell]]s, in the [[retina]], and in many other systems. In such receptors, the signalling molecule (the [[ligand]]) binds to a [[receptor (biochemistry)|receptor]] which 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. By contrast nicotinic receptors use an [[ligand-gated ion channel|ion-gated]] mechanism for signalling. Sufficient ligands cause an [[ion channel]] to open, filling (or evacuating) a cell of a particular ion. ==Receptor isoforms== ===Classification === By the use of selective radioactively-labelled agonist and antagonist substances, four subtypes of muscarinic receptors have been determined, named M<sub>1</sub>-M<sub>4</sub> (using an upper case M and subscript number).<ref name="pmid9647869">{{cite journal | author = Caulfield MP, Birdsall NJ | title = International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors | journal = Pharmacol. Rev. | volume = 50 | issue = 2 | pages = 279–90 | year = 1998 | pmid = 9647869 | issn = | url = http://pharmrev.aspetjournals.org/cgi/content/abstract/50/2/279 }}</ref> For example, the drug [[pirenzepine]] is a muscarinic antagonist (decreases the effect of ACh) which is much more potent at M<sub>1</sub> receptors than it is at other subtypes. The acceptance of the various subtypes has proceeded in numerical order: therefore, sources exist which only recognise the M<sub>1</sub>/M<sub>2</sub> distinction, more recent studies tend to recognise M<sub>3</sub>, and the most recent M<sub>4</sub>. ===Genetic differences=== Meanwhile, [[geneticist]]s and [[molecular biologist]]s have characterised five genes which appear to encode muscarinic receptors, named m1-m5 (lower case m; no subscript number). The first four code for pharmacologic types M<sub>1</sub>-M<sub>4</sub>. The fifth, m5, corresponds to a subtype of receptor which has not been detected pharmacologically. m1 and m2 were determined based upon partial sequencing of M<sub>1</sub> and M<sub>2</sub> receptor proteins, the others were found by searching for homology, using [[bioinformatic]] techniques. ===Difference in G proteins=== {{Seealso|G-proteins}} G proteins contain an alpha-subunit which 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<sub>s</sub>, G<sub>i</sub>, G<sub>q</sub> and G<sub>12/13</sub>.<ref name="pmid1902986">{{cite journal | author = Simon MI, Strathmann MP, Gautam N | title = Diversity of G proteins in signal transduction | journal = Science | volume = 252 | issue = 5007 | pages = 802–8 | year = 1991 | pmid = 1902986 | doi = 10.1126/science.1902986 }}</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<sub>s</sub> and some subtypes of G<sub>i</sub> (G<sub>αt</sub> and G<sub>αg</sub>) are succeptible to CTX. Only G<sub>i</sub> is succeptible to PTX, with the exception of one subtype of G<sub>i</sub> (G<sub>αz</sub>) 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 | author = 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 = J. Biol. Chem. | volume = 268 | issue = 8 | pages = 5676–85 | year = 1993 | pmid = 8449930 | issn = | url = http://www.jbc.org/cgi/content/abstract/268/8/5676 }}</ref> The various G-protein subunits act differently upon secondary messengers, upregulating Phospholipases, downregulating cAMP, and so on. Because of the strong correlations to muscarinic receptor type, CTX and PTX are useful experimental tools in investigating these receptors. ===Comparison of types=== {| class="wikitable" | '''Type''' || '''Gene''' || '''Function''' || '''[[pertussis toxin|PTX]]''' || '''[[Cholera toxin|CTX]]''' || '''Effectors''' || '''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 = 81-8061-187-6 | oclc = }} if nothing else mentioned in table</ref> || '''Antagonists'''<ref name="Tripathi_2004" /> |- | '''[[Muscarinic acetylcholine receptor M1|M<sub>1</sub>]]''' || {{Gene|CHRM1}}|| *[[excitatory postsynaptic potential|EPSP]] in [[autonomic ganglia]] * secretion from [[salivary gland]]s and [[stomach]] * In [[central nervous system|CNS]] (memory?) <ref name=Rang/> || no <BR> (yes) || no <BR> (yes) || [[Gq alpha subunit|G<sub>q</sub>]] <BR> ([[Gi alpha subunit|G<sub>i</sub>]]) <BR> ([[Gs alpha subunit|G<sub>s</sub>]]): <BR> Slow [[EPSP]]. <BR> &darr; [[potassium|K<sup>+</sup>]] conductance <ref name=Rang/><ref name="pmid1693682">{{cite journal | author = Uchimura N, North RA | title = Muscarine reduces inwardly rectifying potassium conductance in rat nucleus accumbens neurones | journal = J. Physiol. (Lond.) | volume = 422 | issue = | pages = 369–80 | year = 1990 | pmid = 1693682 | doi = | issn = | url = http://jp.physoc.org/cgi/content/abstract/422/1/369 }}</ref>|| *[[acetylcholine]] *[[oxotremorine]] *[[carbachol]]<ref name=Rang>{{cite book | first = | last =Rang HP, Dale MM, Ritter JM, Moore PK| authorlink = | coauthors = | year = 2003| month = | title = Pharmacology | chapter = Ch. 10 | editor = | others = | edition = 5<sup>th</sup> edition | pages = page 139 | publisher = Elsevier Churchill Livingstone| location = | id = ISBN 0-443-07145-4| url = }}</ref> *[[McNA343]]<ref name=Rang/> || *[[atropine]]<ref name=Rang/> *[[scopolamine]]<ref name=Rang/> *[[dicycloverine]]<ref name=Rang/> *[[tolterodine]]<ref name=Rang/> *[[oxybutynin]]<ref name=Rang/> *[[ipratropium]]<ref name=Rang/> *[[mamba toxin]] MT7<ref name=Rang/> *[[pirenzepine]] *[[telenzepine]] |- | '''[[Muscarinic acetylcholine receptor M2|M<sub>2</sub>]]''' || {{Gene|CHRM2}} || *slow [[heart rate]] *reduce contractile forces of [[heart atrium|atrium]] *reduce conduction velocity of [[atrioventricular node|AV node]] *In [[central nervous system|CNS]] *[[homotropic inhibition]] || yes || no || [[Gi alpha subunit|G<sub>i</sub>]] <BR> &uarr; [[potassium|K<sup>+</sup>]] conductance <ref name=Rang/> <BR> &darr; [[calcium|Ca<sup>2+</sup>]] conductance <ref name=Rang/> || *[[acetylcholine]] *[[methacholine]] *[[carbachol]]<ref name=Rang/> *[[oxotremorine]] <ref name=Rang/> || *[[atropine]]<ref name=Rang/> *[[dicycloverine]]<ref name=Rang/> *[[tolterodine]]<ref name=Rang/> *[[oxybutynin]]<ref name=Rang/> *[[ipratropium]]<ref name=Rang/> *[[methoctramine]] *[[tripitamine]] *[[gallamine]] |- | '''[[Muscarinic acetylcholine receptor M3|M<sub>3</sub>]]''' || {{Gene|CHRM3}} || *smooth muscle contraction *increased [[endocrine gland|endocrine]] and [[exocrine gland]] secretions, e.g. [[salivary glands]] and [[stomach]] *In [[central nervous system|CNS]] *[[Accommodation (eye)|Eye accommodation]] *[[vasodilation]] *induce [[emesis]] || no || no || [[Gq alpha subunit|G<sub>q</sub>]] || *[[acetylcholine]] *[[bethanechol]] *[[carbachol]]<ref name=Rang/> *[[oxotremorine]]<ref name=Rang/> *[[pilocarpine]] (in eye) || *[[atropine]]<ref name=Rang/> *[[dicycloverine]]<ref name=Rang/> *[[tolterodine]]<ref name=Rang/> *[[oxybutynin]]<ref name=Rang/> *[[ipratropium]]<ref name=Rang/> *[[darifenacin]] *[[tiotropium]] |- | '''[[Muscarinic acetylcholine receptor M4|M<sub>4</sub>]]''' || {{Gene|CHRM4}} || * Enhanced locomotion <ref name=Rang/> *In [[central nervous system|CNS]] || yes || ? || [[Gi alpha subunit|G<sub>i</sub>]] <BR> &uarr; [[potassium|K<sup>+</sup>]] conductance <ref name=Rang/> <BR> &darr; [[calcium|Ca<sup>2+</sup>]] conductance <ref name=Rang/> || *[[acetylcholine]] *[[carbachol]]<ref name=Rang/> *[[oxotremorine]] <ref name=Rang/> || *[[atropine]]<ref name=Rang/> *[[dicycloverine]]<ref name=Rang/> *[[tolterodine]]<ref name=Rang/> *[[oxybutynin]]<ref name=Rang/> *[[ipratropium]]<ref name=Rang/> *[[mamba toxin]] MT3<ref name=Rang/> |- | '''[[Muscarinic acetylcholine receptor M5|M<sub>5</sub>]]''' || [[CHRM5]] || *In [[central nervous system|CNS]] || no || ? || [[Gq alpha subunit|G<sub>q</sub>]] || *[[acetylcholine]] *[[carbachol]]<ref name=Rang/> *[[oxotremorine]] <ref name=Rang/> || *[[atropine]]<ref name=Rang/> *[[dicycloverine]]<ref name=Rang/> *[[tolterodine]]<ref name=Rang/> *[[oxybutynin]]<ref name=Rang/> *[[ipratropium]]<ref name=Rang/> |} ===M<sub>1</sub> receptor=== {{Main|Muscarinic acetylcholine receptor M1}} This receptor is found mediating slow [[excitatory postsynaptic potential|EPSP]] at the ganglion in the postganglionic nerve,<ref name="Messer_2000">{{cite web |url= http://www.neurosci.pharm.utoledo.edu/MBC3320/acetylcholine.htm |title= Acetylcholine|accessdate=2007-10-27 |author= Messer, Jr, WS | date= 2000-01-20 |publisher= University of Toledo }}</ref> 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 ed. | pages = 311 pages | isbn = 1-55009-109-3 | 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 |accessdate=2007-10-27 |author = Richelson, Elliott | date= 2000 |publisher= American College of Neuropsychopharmacology }}</ref> It is predominantly found bound to G proteins of class [[Gq alpha subunit|G<sub>q</sub>]]<ref name="pmid8645172">{{cite journal | author = Burford NT, Nahorski SR | title = Muscarinic M<sub>1</sub> 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 = Biochem. J. | volume = 315 ( Pt 3) | issue = | pages = 883–8 | year = 1996 | pmid = 8645172 | issn = | url = http://www.biochemj.org/bj/315/bj3150883.htm }}</ref> which use upregulation of [[phospholipase]] C and therefore [[inositol trisphosphate]] and intracellular calcium as a signalling pathway. A receptor so bound would not be susceptible to CTX or PTX. However, G<sub>i</sub> (causing a downstream decrease in [[cyclic_adenosine_monophosphate|cAMP]]) and G<sub>s</sub> (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. ===M<sub>2</sub> receptor=== {{Main|Muscarinic acetylcholine receptor M2}} The M<sub>2</sub> muscarinic receptors are located in the heart, where they act to slow the [[heart rate]] down to normal [[sinus rhythm]] after stimulatory actions of the sympathetic nervous system, by slowing the speed of [[depolarization]]. They also reduce contractile forces of the [[heart atrium|atrial]] [[cardiac muscle]], and reduce conduction velocity of the [[atrioventricular node]] (AV node). However, they have no effect on the contractile forces of the [[heart ventricle|ventricular]] muscle. M<sub>2</sub> muscarinic receptors act via a [[Gi alpha subunit|G<sub>i</sub>]] type receptor, which causes a decrease in cAMP in the cell, generally leading to inhibitory-type effects. ===M<sub>3</sub> receptor=== {{Main|Muscarinic acetylcholine receptor M3}} The M<sub>3</sub> 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 M<sub>3</sub> receptor is G<sub>q</sub>-coupled and mediates an increase in intracellular calcium, it typically causes constriction of smooth muscle, such as that observed during [[bronchoconstriction]]. However, with respect to vasculature, activation of M<sub>3</sub> on vascular endothelial cells causes increased synthesis of nitric oxide which diffuses to adjacent vascular smooth muscle cells and causes their relaxation thereby explaining the paradoxical effect of parasympathomimetics on vascular tone and bronchiolar tone. Indeed, direct stimulation of vascular smooth muscle M<sub>3</sub> mediates vasconstriction in pathologies whereby the vascular endothelium is disrupted.<ref name="isbn0-07-142280-3">{{cite book | author = Keith Parker; Laurence Brunton; Goodman, Louis Sanford; Lazo, John S.; Gilman, Alfred | title = Goodman & Gilman's the pharmacological basis of therapeutics | publisher = McGraw-Hill | location = New York | edition = 11<sup>th</sup> Ed. | year = 2006 | pages = page 185 | isbn = 0-07-142280-3 | oclc = }}</ref> The M<sub>3</sub> receptors are also located in many glands which help to stimulate secretion in salivary glands and other glands of the body. Like the M<sub>1</sub> muscarinic receptor, M<sub>3</sub> receptors are G proteins of class [[Gq alpha subunit|G<sub>q</sub>]] which upregulate phospholipase C and therefore inositol trisphosphate and intracellular calcium as a signalling pathway. ===M<sub>4</sub> receptor=== {{Main|Muscarinic acetylcholine receptor M4}} M<sub>4</sub> receptors are found in the CNS. Receptors work via [[Gi alpha subunit|G<sub>i</sub>]] receptors to decrease cAMP in the cell and thus produce generally inhibitory effects. ===M<sub>5</sub> receptor=== {{Main|Muscarinic acetylcholine receptor M5}} Location of M<sub>5</sub> receptors are not well known. Like the M<sub>1</sub> and M<sub>3</sub> muscarinic receptor, M<sub>5</sub> receptors are coupled with G proteins of class [[Gq alpha subunit|G<sub>q</sub>]] which upregulate phospholipase C and therefore inositol trisphosphate and intracellular calcium as a signalling pathway. == See also == * [[Nicotinic acetylcholine receptor]] * [[Muscarinic receptor agonist]] * [[Tiotropium]] == References == {{Reflist|2}} ==External links== *[http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1271 IUPHAR GPCR Database - Muscarinic Acetylcholine Receptors] * {{MeshName|Receptors,+Muscarinic}} {{G protein-coupled receptors}} [[Category:G protein coupled receptors]] [[Category:Neurochemistry]] [[Category:Neurophysiology]] [[de:Muskarinischer Acetylcholinrezeptor]] [[es:Receptor muscarínico]] [[fr:Récepteur muscarinique]] [[it:Recettore muscarinico]] [[pl:Receptory muskarynowe]] [[pt:Receptor muscarínico]] [[uk:Мускариновий ацетилхоліновий рецептор]] [[zh:蕈毒鹼型乙醯膽鹼受器]]