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Amanita muscaria, the mushroom from which muscarine was isolated.

Acetylcholine - the natural agonist of muscarinic and nicotinic receptors.

Muscarine - an agonist used to distinguish between these two classes of receptors. Not normally found in the body.

Atropine - an antagonist.

Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-receptor complexes in the cell membranes of certain neurons^[1] and other cells. They play several roles, including acting as the main end-receptor stimulated by acetylcholine released from postganglionic fibers in the parasympathetic nervous system.

Muscarinic receptors were named as such because they are more sensitive to muscarine than to nicotine.^[2] Their counterparts are nicotinic acetylcholine receptors (nAChRs), receptor ion channels that are also important in the autonomic nervous system. Many drugs and other substances (for example pilocarpine and scopolamine) manipulate these two distinct receptors by acting as selective agonists or antagonists.^[3]

1 Function
- 1.1 Recovery receptors
- 1.2 Postganglionic neurons
- 1.3 Innervated tissue
- 1.4 Higher central nervous system
- 1.5 Presynaptic membrane of the neuromuscular junction
2 Form of muscarinic receptors
3 Receptor isoforms
- 3.1 Classification
- 3.2 Genetic differences
- 3.3 Difference in G proteins
- 3.4 M₁ receptor
- 3.5 M₂ receptor
- 3.6 M₃ receptor
- 3.7 M₄ receptor
- 3.8 M₅ receptor
4 Pharmacological application
5 See also
6 References
7 External links

Function

Acetylcholine (ACh) is a neurotransmitter found extensively in the brain and the autonomic ganglia. Muscarinic receptors are used in the following roles:

Recovery receptors

The structure of Muscarinic acetylcholine receptor M2

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) 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]}.

Peripheral autonomic fibers (sympathetic and parasympathetic fibers) are categorized anatomically as either preganglionic or postganglionic fibers, then further generalized as either adrenergic fibers, with their corresponding adrenergic receptors, or cholinergic fibers, with their cholinergic receptors. Both preganglionic sympathetic fibers and preganglionic parasympathetic fibers are cholinergic. All postganglionic sympathetic fibers are adrenergic; their neurotransmitter is norepinephrine, except for the postganglionic sympathetic fibers to the sweat glands, piloerectile muscles of the body hairs, and the skeletal muscle arterioles.

The adrenal medulla is considered a sympathetic ganglion and, like other sympathetic ganglia, is supplied by cholinergic preganglionic sympathetic fibers; acetylcholine is its neurotransmitter. The other postganglionic fibers of the peripheral autonomic system belong to the parasympathetic division; all are cholinergic fibers, and use acetylcholine (ACh) as their neurotransmitter.

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.

Innervated tissue

Very few parts of the sympathetic system use cholinergic receptors. In sweat glands the receptors are of the muscarinic type. The sympathetic nervous system also has some preganglionic nerves terminating at the chromaffin cells in the adrenal medulla, which secrete epinephrine and norepinephrine into the bloodstream. Some believe that chromaffin cells are modified postganglionic CNS fibers. In the adrenal medulla, acetylcholine is used as a neurotransmitter, and the receptor is of the nicotinic type.

The somatic nervous system uses a nicotinic receptor to acetylcholine at the neuromuscular junction.

Higher central nervous system

Muscarinic acetylcholine 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.

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.

Form of muscarinic receptors

Muscarinic acetylcholine receptors belong to a class of metabotropic receptors that use G proteins as their signalling mechanism. In such receptors, the signaling molecule (the ligand) binds to a receptor that has seven transmembrane regions; 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.^[4]

By contrast, nicotinic receptors 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) of ion (e.g., K⁺, Na⁺, Ca²⁺) to diffuse into or out of the cell.

Receptor isoforms

Classification

By the use of selective radioactively labeled agonist and antagonist substances, five subtypes of muscarinic receptors have been determined, named M₁-M₅ (using an upper case M and subscript number).^[5] M₁,M₃,M₅ receptors are coupled with Gq proteins, while M₂ and M₄ receptors are coupled with G_i/o proteins.^[4] 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, sources that recognize only the M₁/M₂ distinction exist. More recent studies tend to recognize M₃ and the most recent M₄.

Genetic differences

Meanwhile, geneticists and molecular biologists have characterised five genes that appear to encode muscarinic receptors, named m1-m5 (lowercase m; no subscript number). The first four 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.

Difference in G proteins

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.^[6] 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.^[7]

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
Type	Gene	Function	PTX	CTX	Effectors	Agonists^[8]	Antagonists^[8]
M₁	CHRM1	EPSP in autonomic ganglia secretion from salivary glands and stomach In CNS activates slow after-depolarizing potentials in neurons ^[9]^[10] ^[11]	no (yes)	no (yes)	G_q (G_i) (G_s): Slow EPSP. ↓ K⁺ conductance^[11]^[12]	acetylcholine oxotremorine muscarine carbachol^[11] McNA343^[11] 77-LH-28-1	atropine^[11] Hyoscyamine^[13] scopolamine^[11] Diphenhydramine Dimenhydrinate dicycloverine^[11] Thorazine tolterodine^[11] oxybutynin^[11] ipratropium^[11] mamba toxin MT7^[11] mamba toxin MT1^[14] mamba toxin MT2^[15] pirenzepine telenzepine chlorpromazine haloperidol
M₂	CHRM2	slow heart rate reduce contractile forces of atrium reduce conduction velocity of AV node In CNS homotropic inhibition	yes	no	G_i ↑ K⁺ conductance^[11] ↓ Ca²⁺ conductance^[11]	acetylcholine methacholine carbachol^[11] oxotremorine^[11] muscarine	atropine^[11] hyoscyamine^[13] dicycloverine^[11] Thorazine Diphenhydramine Dimenhydrinate tolterodine^[11] oxybutynin^[11] ipratropium^[11] methoctramine^[16] tripitramine gallamine chlorpromazine
M₃	CHRM3	smooth muscle contraction bronchoconstriction Increase intracellular calcium in vascular endothelium increased endocrine and exocrine gland secretions, e.g. salivary glands and stomach In CNS Eye accommodation vasodilation induce emesis	no	no	G_q	acetylcholine^[4] bethanechol carbachol^[11]^[4] oxotremorine^[11] pilocarpine (in eye)	atropine^[11]^[4] hyoscyamine^[13] Diphenhydramine Dimenhydrinate dicycloverine^[11] tolterodine^[11] oxybutynin^[11] ipratropium^[11] darifenacin tiotropium
M₄	CHRM4	Activation of M4 causes decreased locomotion^[11] In CNS	yes	?	G_i ↑ K⁺ conductance^[11] ↓ Ca²⁺ conductance^[11]	acetylcholine carbachol^[11] oxotremorine^[11]	atropine^[11] Diphenhydramine Dimenhydrinate dicycloverine^[11] tolterodine^[11] oxybutynin^[11] ipratropium^[11] mamba toxin MT1^[14] mamba toxin MT2^[15] mamba toxin MT3^[11]
M₅	CHRM5	In CNS	no	?	G_q	acetylcholine carbachol^[11] oxotremorine^[11]	atropine^[11] Diphenhydramine Dimenhydrinate dicycloverine^[11] tolterodine^[11] oxybutynin^[11] ipratropium^[11]

M₁ receptor

This receptor is found mediating slow EPSP at the ganglion in the postganglionic nerve^{[citation needed]}, is common in exocrine glands and in the CNS.^[17]^[18]

It is predominantly found bound to G proteins of class G_q,^[19] 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 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.

M₂ receptor

The M₂ 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 atrial cardiac muscle, and reduce conduction velocity of the atrioventricular node (AV node). It also serves to slightly decrease the contractile forces of the ventricular muscle.

M₂ muscarinic receptors act via a G_i type receptor, which causes a decrease in cAMP in the cell, inhibition of voltage-gated Ca²⁺ channels, and increasing efflux of K⁺, in general, leading to inhibitory-type effects.

M₃ receptor

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 bladder voiding.^[20] However, with respect to vasculature, activation of M₃ 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, M₃ mediates vasconstriction in pathologies wherein the vascular endothelium is disrupted.^[21] The M₃ receptors are also located in many glands, which help to stimulate secretion in, for example, the salivary glands, as well as other glands of the body.

Like the M₁ muscarinic receptor, M₃ receptors are G proteins of class G_q that upregulate phospholipase C and, therefore, inositol trisphosphate and intracellular calcium as a signaling pathway.^[4]

M₄ receptor

M₄ receptors are found in the CNS.

Receptors work via G_i receptors to decrease cAMP in the cell and, thus, produce generally inhibitory effects. Possible bronchospasm may result if stimulated by muscarinic agonists

M₅ receptor

Location of M₅ receptors is not well known.

Like the M₁ and M₃ muscarinic receptor, M₅ receptors are coupled with G proteins of class G_q that upregulate phospholipase C and, therefore, inositol trisphosphate and intracellular calcium as a signaling pathway.

Pharmacological application

Ligands targeting the mAChR that are currently approved for clinical use include non-selective antagonists for the treatment of Parkinson's disease,^[22] atropine (to dilate the pupil), Scopolamine (used to prevent motion sickness), and ipratropium (used in the treatment of COPD).^[3]

References

^ Eglen RM (July 2006). "Muscarinic receptor subtypes in neuronal and non-neuronal cholinergic function". Auton Autacoid Pharmacol 26 (3): 219–33. doi:10.1111/j.1474-8673.2006.00368.x. PMID 16879488.
^ Ishii M, Kurachi Y (2006). "Muscarinic acetylcholine receptors". Curr. Pharm. Des. 12 (28): 3573–81. doi:10.2174/138161206778522056. PMID 17073660.
^ ^a ^b Purves, Dale, George J. Augustine, David Fitzpatrick, William C. Hall, Anthony-Samuel LaMantia, James O. McNamara, and Leonard E. White (2008). Neuroscience. 4th ed. Sinauer Associates. pp. 122–6. ISBN 978-0-87893-697-7.
^ ^a ^b ^c ^d ^e ^f Qin K, Dong C, Wu G, Lambert NA (August 2011). "Inactive-state preassembly of Gq-coupled receptors and Gq heterotrimers". Nature Chemical Biology 7 (11): 740–747. doi:10.1038/nchembio.642. PMC 3177959. PMID 21873996.
^ Caulfield MP, Birdsall NJ (1 June 1998). "International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors". Pharmacol. Rev. 50 (2): 279–90. PMID 9647869.
^ Simon MI, Strathmann MP, Gautam N (1991). "Diversity of G proteins in signal transduction". Science 252 (5007): 802–8. doi:10.1126/science.1902986. PMID 1902986.
^ Dell'Acqua ML, Carroll RC, Peralta EG (15 March 1993). "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". J. Biol. Chem. 268 (8): 5676–85. PMID 8449930.
^ ^a ^b Tripathi KD (2004). Essentials of Medical Pharmacology (5th ed.). India: Jaypee Brothers, Medical Publishers. pp. 890 pages. ISBN 81-8061-187-6. if nothing else mentioned in table
^ Smith, Richard; Araneda, Ricardo (2010). "Cholinergic modulation of neuronal excitability in the accessory olfactory bulb". Journal of Neurophysiology 106: 2963–2974. doi:10.1152/jn.00446.2010. PMID 20861438. Retrieved 15 July 2015.
^ Egorov, Alexei (2002). "Graded persistent activity in entorhinal cortex neurons". Nature 420: 173–178. doi:10.1038/nature01171. PMID 12432392. Retrieved 15 July 2015.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t ^u ^v ^w ^x ^y ^z ^aa ^ab ^ac ^ad ^ae ^af ^ag ^ah ^ai ^aj ^ak ^al ^am ^an ^ao ^ap ^aq ^ar ^as Rang HP, Dale MM, Ritter JM, Moore PK (2003). "Ch. 10". Pharmacology (5th ed.). Elsevier Churchill Livingstone. p. 139. ISBN 0-443-07145-4.
^ Uchimura N, North RA (1990). "Muscarine reduces inwardly rectifying potassium conductance in rat nucleus accumbens neurones". J. Physiol. (Lond.) 422 (1): 369–80. PMC 1190137. PMID 1693682.
^ ^a ^b ^c Edwards Pharmaceuticals, Inc.; Belcher Pharmaceuticals, Inc. (May 2010). "DailyMed". U.S. National Library of Medicine. Retrieved January 13, 2013.
^ ^a ^b Servent D, Blanchet G, Mourier G, Marquer C, Marcon E, Fruchart-Gaillard C (August 2011). "Muscarinic toxins". Toxicon 58 (6-7): 455–463. doi:10.1016/j.toxicon.2011.08.004. PMID 21906611.
^ ^a ^b Karlsson E, Jolkkonen M, Mulugeta E, Onali P, Adem A (September 2000). "Snake toxins with high selectivity for subtypes of muscarinic acetylcholine receptors.". Biochimie 82 (9-10): 793–806. doi:10.1016/S0300-9084(00)01176-7. PMID 11086210.
^ Melchiorre C, Angeli P, Lambrecht G, Mutschler E, Picchio MT, Wess J (December 1987). "Antimuscarinic action of methoctramine, a new cardioselective M-2 muscarinic receptor antagonist, alone and in combination with atropine and gallamine". European Journal of Pharmacology 144 (2): 117–124. doi:10.1016/0014-2999(87)90509-7. PMID 3436364.
^ Johnson, Gordon (2002). PDQ Pharmacology (2nd ed.). Hamilton, Ontario: BC Decker Inc. pp. 311 pages. ISBN 1-55009-109-3.
^ Richelson, Elliott (2000). "Cholinergic Transduction, Psychopharmacology - The Fourth Generation of Progress". American College of Neuropsychopharmacology. Retrieved 2007-10-27.
^ Burford NT, Nahorski SR (1996). "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". Biochem. J. 315 (3): 883–8. PMC 1217289. PMID 8645172.
^ Moro C, Uchiyama J, Chess-Williams R (December 2011). "Urothelial/lamina propria spontaneous activity and the role of M3 muscarinic receptors in mediating rate responses to stretch and carbachol". Urology. 76 (6): 1442.e9–15. doi:10.1016/j.urology.2011.08.039. PMID 22001099.
^ Keith Parker; Laurence Brunton; Goodman, Louis Sanford; Lazo, John S.; Gilman, Alfred (2006). Goodman & Gilman's the pharmacological basis of therapeutics (11th ed.). New York: McGraw-Hill. p. 185. ISBN 0-07-142280-3.
^ Langmead CJ, Watson J, Reavill C (February 2008). "Muscarinic acetylcholine receptors as CNS drug targets". Pharmacol. Ther. 117 (2): 232–43. doi:10.1016/j.pharmthera.2007.09.009. PMID 18082893.

External links

"Acetylcholine Receptors (Muscarinic)". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
Receptors, Muscarinic at the US National Library of Medicine Medical Subject Headings (MeSH)

UpToDate Contents

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1. オトギリソウの臨床使用 clinical use of st johns wort

English Journal

M1 muscarinic acetylcholine receptor interacts with BACE1 and regulates its proteosomal degradation.

Jiang S, Wang Y, Ma Q, Zhou A, Zhang X, Zhang YW.SourceFujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, College of Medicine, Xiamen University, Xiamen, Fujian 361005, People's Republic of China.
Neuroscience letters.Neurosci Lett.2012 May 2;515(2):125-30. Epub 2012 Mar 19.
A prime culprit in the pathogenesis of Alzheimer's disease (AD) is overproduction/aggregation of β-amyloid (Aβ), which is derived from β-Amyloid Precursor Protein through sequential cleavages by β-site APP cleaving protein 1 (BACE1) and γ-secretase. The level/activity of BACE1 is elevated in sp
PMID 22450048

Elevated mercury exposure and neurochemical alterations in little brown bats (Myotis lucifugus) from a site with historical mercury contamination.

Nam DH, Yates D, Ardapple P, Evers DC, Schmerfeld J, Basu N.SourceDepartment of Environmental Health Sciences, University of Michigan School of Public Health, Ann Arbor, MI, 48109, USA.
Ecotoxicology (London, England).Ecotoxicology.2012 May;21(4):1094-101. Epub 2012 Feb 14.
Despite evidence of persistent methylmercury (MeHg) contamination in the South River (Virginia, USA) ecosystem, there is little information concerning MeHg-associated neurological impacts in resident wildlife. Here we determined mercury (Hg) concentrations in tissues of insectivorous little brown ba
PMID 22331394

Japanese Journal

Selective M3 Muscarinic Receptor Antagonist Inhibits Small-Cell Lung Carcinoma Growth in a Mouse Orthotopic Xenograft Model

Ami Nozomi,Koga Kazumi,Fushiki Hiroshi,Ueno Yoko,Ogino Yoshio,Ohta Hisashi
Journal of Pharmacological Sciences 116(1), 81-88, 2011
… In small cell lung carcinoma (SCLC), acetylcholine (ACh) is synthesized and secreted, and it acts as an autocrine growth factor through activation of its receptors, muscarinic receptor (mAChR) and nicotinic receptor (nAChR). … Alteration of tumor growth by blockade of M3 mAChR in a human SCLC cell line, NCI-H82, was investigated in the present study. …
NAID 130000663531

アセチルコリンのルーツと非神経性アセチルコリン

川島紘一郎
基礎老化研究 34(4), 12-24, 2010-11-04
NAID 10027470313

Preferential Localization of Muscarinic M1 Receptor on Dendritic Shaft and Spine of Cortical Pyramidal Cells and Its Anatomical Evidence for Volume Transmission

Yamasaki Miwako,Matsui Minoru,Watanabe Masahiko
Journal of Neuroscience 30(12), 4408-4418, 2010-03-24
… However, it remains inconclusive whether the mode of ACh-mAChR signaling is synaptic, so-called "wired," transmission mediated by ACh released into the synaptic cleft, or nonsynaptic, so-called "volume," transmission by ambient ACh. … To address this issue, we examined cellular and subcellular distribution of M1, the most predominant mAChR subtype in the cerebral cortex and hippocampus, and pursued its anatomical relationship with cholinergic varicosities in these regions of adult mice. …
NAID 120002414847

Related Pictures

★リンクテーブル★

リンク元	「ムスカリン受容体」

「ムスカリン受容体」

　　[★]

英: muscarinic receptor
同: ムスカリン性受容体、ムスカリン性アセチルコリン受容体 muscarinic cholinergic receptors mAChR
関: アセチルコリン受容体、ニコチン受容体、ムスカリン受容体拮抗薬、受容体

アセチルコリン受容体のサブタイプ
7回膜貫通型のGタンパク質共役型受容体　→ニコチン受容体はイオンチャネル型

β-アドレナリン受容体などと類似の構造と機能を有する (SPC.66)

M₁受容体は自律神経節の節後ニューロンでslow EPSPの発生に関与 (⇔N_Nはfast EPSPの発生に関与) (SP.412)
M₂受容体は心臓に抑制的
M₃受容体は平滑筋収縮、分泌線分泌促進