Muscarinic acetylcholine receptor M3

Cholinergic receptor, muscarinic 3
Identifiers
Symbols	CHRM3; HM3
External IDs	OMIM: 118494 MGI: 88398 HomoloGene: 20191 IUPHAR: M3 GeneCards: CHRM3 Gene
Gene Ontology Molecular function • phosphatidylinositol phospholipase C activity • receptor activity • G-protein coupled receptor activity • muscarinic acetylcholine receptor activity • drug binding • acetylcholine binding Cellular component • plasma membrane • plasma membrane • integral to plasma membrane • basolateral plasma membrane • cell junction • dendrite • asymmetric synapse • axon terminus • postsynaptic membrane Biological process • regulation of vascular smooth muscle contraction • energy reserve metabolic process • protein modification process • signal transduction • G-protein coupled receptor protein signaling pathway • muscarinic acetylcholine receptor signaling pathway • nervous system development • digestion • cell proliferation • positive regulation of smooth muscle contraction • regulation of insulin secretion Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	1131	12671
Ensembl	ENSG00000133019	ENSMUSG00000046159
UniProt	P20309	Q542R4
RefSeq (mRNA)	XM_001130695	NM_033269.4
RefSeq (protein)	XP_001130695	NP_150372.1
Location (UCSC)	Chr 1: 239.55 – 240.08 Mb	Chr 13: 9.88 – 9.88 Mb
PubMed search	[1]	[2]

The muscarinic acetylcholine receptor M₃, also known as the cholinergic receptor, muscarinic 3, is a muscarinic acetylcholine receptor. It is encoded by the human gene CHRM3.^[1]

The M₃ muscarinic receptors are located at many places in the body, e.g., smooth muscles, the endocrine glands, the exocrine glands, as well as the lungs. They are also found in the CNS, where they induce emesis. In general, they cause smooth muscle contraction and increased glandular secretions.^[1]

They are unresponsive to PTX and CTX.

Mechanism

Like the M₁ muscarinic receptor, M₃ receptors are coupled to G proteins of class G_q, which upregulate phospholipase C and, therefore, inositol trisphosphate and intracellular calcium as a signalling pathway. The calcium function in vertebrates also involves activation of protein kinase C and its effects.

Effects

Smooth muscle

Because the M₃ receptor is G_q-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 M₃ on vascular endothelial cells causes increased synthesis of nitric oxide, which diffuses to adjacent vascular smooth muscle cells and causes their relaxation and vasodilation, thereby explaining the paradoxical effect of parasympathomimetics on vascular tone and bronchiolar tone. Indeed, direct stimulation of vascular smooth muscle M₃ mediates vasoconstriction in pathologies wherein the vascular endothelium is disrupted.^[2]

Other

The M₃ receptors are also located in many glands, both endocrine and exocrine glands, and help to stimulate secretion in salivary glands and other glands of the body.

Other effects are:

• increased secretions from stomach
• Eye accommodation

Agonists

No highly selective M3 agonists are yet available as of 2009, but a number of non-selective muscarinic agonists are active at M3.

• acetylcholine
• bethanechol
• carbachol^[3]
• L-689,660 (mixed M1/M3 agonist)
• oxotremorine^[3]
• pilocarpine (in eye)

Antagonists

• atropine^[3]
• 4-DAMP (1,1-Dimethyl-4-diphenylacetoxypiperidinium iodide, CAS# 1952-15-4)
• DAU-5884 (8-Methyl-8-azabicyclo-3-endo[1.2.3]oct-3-yl-1,4-dihydro-2-oxo-3(2H)-quinazolinecarboxylic acid ester, CAS# 131780-47-7)
• dicycloverine^[3]
• J-104,129 ((aR)-a-Cyclopentyl-a-hydroxy-N-[1-(4-methyl-3-pentenyl)-4-piperidinyl]benzeneacetamide, CAS# 244277-89-2)
• HL-031,120 ((3R,2'R)-enantiomer of EA-3167)
• tolterodine^[3]
• oxybutynin^[3]
• ipratropium^[3]
• darifenacin
• tiotropium
• Zamifenacin ((3R)-1-[2-(1-,3-Benzodioxol-5-yl)ethyl]-3-(diphenylmethoxy)piperidine, CAS# 127308-98-9)

Interactions

Muscarinic acetylcholine receptor M3 has been shown to interact with Arf6^[4] and ARF1.^[4]

See also

• Muscarinic acetylcholine receptor

References

1. ^ ^{a b} "Entrez Gene: CHRM3 cholinergic receptor, muscarinic 3". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1131. 
2. ^ 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. pp. page 185. ISBN 0-07-142280-3. 
3. ^ ^{a b c d e f g} Rang HP, Dale MM, Ritter JM, Moore PK (2003). "Ch. 10". Pharmacology (5th ed.). Elsevier Churchill Livingstone. pp. page 139. ISBN 0-443-07145-4. 
4. ^ ^{a b} Mitchell, Rory; Robertson Derek N, Holland Pamela J, Collins Daniel, Lutz Eve M, Johnson Melanie S (September 2003). "ADP-ribosylation factor-dependent phospholipase D activation by the M3 muscarinic receptor". J. Biol. Chem. (United States) 278 (36): 33818–30. doi:10.1074/jbc.M305825200. ISSN 0021-9258. PMID 12799371. 

External links

• "Acetylcholine receptors (muscarinic): M₃". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2143. 

Further reading

• Goyal RK; Underhill, Lisa H.; Goyal, Raj K. (1989). "Muscarinic receptor subtypes. Physiology and clinical implications.". N. Engl. J. Med. 321 (15): 1022–9. doi:10.1056/NEJM198910123211506. PMID 2674717. 
• Eglen RM, Reddy H, Watson N, Challiss RA (1994). "Muscarinic acetylcholine receptor subtypes in smooth muscle.". Trends Pharmacol. Sci. 15 (4): 114–9. doi:10.1016/0165-6147(94)90047-7. PMID 8016895. 
• Brann MR, Ellis J, Jørgensen H, et al. (1994). "Muscarinic acetylcholine receptor subtypes: localization and structure/function.". Prog. Brain Res. 98: 121–7. doi:10.1016/S0079-6123(08)62388-2. PMID 8248499. 
• Gutkind JS, Novotny EA, Brann MR, Robbins KC (1991). "Muscarinic acetylcholine receptor subtypes as agonist-dependent oncogenes.". Proc. Natl. Acad. Sci. U.S.A. 88 (11): 4703–7. doi:10.1073/pnas.88.11.4703. PMC 51734. PMID 1905013. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=51734. 
• Ashkenazi A, Ramachandran J, Capon DJ (1989). "Acetylcholine analogue stimulates DNA synthesis in brain-derived cells via specific muscarinic receptor subtypes.". Nature 340 (6229): 146–50. doi:10.1038/340146a0. PMID 2739737. 
• Bonner TI, Buckley NJ, Young AC, Brann MR (1987). "Identification of a family of muscarinic acetylcholine receptor genes.". Science 237 (4814): 527–32. doi:10.1126/science.3037705. PMID 3037705. 
• Bonner TI, Young AC, Brann MR, Buckley NJ (1990). "Cloning and expression of the human and rat m5 muscarinic acetylcholine receptor genes.". Neuron 1 (5): 403–10. doi:10.1016/0896-6273(88)90190-0. PMID 3272174. 
• Peralta EG, Ashkenazi A, Winslow JW, et al. (1988). "Distinct primary structures, ligand-binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors.". EMBO J. 6 (13): 3923–9. PMC 553870. PMID 3443095. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=553870. 
• Blin N, Yun J, Wess J (1995). "Mapping of single amino acid residues required for selective activation of Gq/11 by the m3 muscarinic acetylcholine receptor.". J. Biol. Chem. 270 (30): 17741–8. doi:10.1074/jbc.270.30.17741. PMID 7629074. 
• Crespo P, Xu N, Daniotti JL, et al. (1994). "Signaling through transforming G protein-coupled receptors in NIH 3T3 cells involves c-Raf activation. Evidence for a protein kinase C-independent pathway.". J. Biol. Chem. 269 (33): 21103–9. PMID 8063729. 
• Haga K, Kameyama K, Haga T, et al. (1996). "Phosphorylation of human m1 muscarinic acetylcholine receptors by G protein-coupled receptor kinase 2 and protein kinase C.". J. Biol. Chem. 271 (5): 2776–82. doi:10.1074/jbc.271.5.2776. PMID 8576254. 
• Szekeres PG, Koenig JA, Edwardson JM (1998). "The relationship between agonist intrinsic activity and the rate of endocytosis of muscarinic receptors in a human neuroblastoma cell line.". Mol. Pharmacol. 53 (4): 759–65. PMID 9547368. 
• von der Kammer H, Mayhaus M, Albrecht C, et al. (1998). "Muscarinic acetylcholine receptors activate expression of the EGR gene family of transcription factors.". J. Biol. Chem. 273 (23): 14538–44. doi:10.1074/jbc.273.23.14538. PMID 9603968. 
• Ndoye A, Buchli R, Greenberg B, et al. (1998). "Identification and mapping of keratinocyte muscarinic acetylcholine receptor subtypes in human epidermis.". J. Invest. Dermatol. 111 (3): 410–6. doi:10.1046/j.1523-1747.1998.00299.x. PMID 9740233. 
• Goodchild RE, Court JA, Hobson I, et al. (1999). "Distribution of histamine H3-receptor binding in the normal human basal ganglia: comparison with Huntington's and Parkinson's disease cases.". Eur. J. Neurosci. 11 (2): 449–56. doi:10.1046/j.1460-9568.1999.00453.x. PMID 10051746. 
• Sato KZ, Fujii T, Watanabe Y, et al. (1999). "Diversity of mRNA expression for muscarinic acetylcholine receptor subtypes and neuronal nicotinic acetylcholine receptor subunits in human mononuclear leukocytes and leukemic cell lines.". Neurosci. Lett. 266 (1): 17–20. doi:10.1016/S0304-3940(99)00259-1. PMID 10336173. 
• Budd DC, McDonald JE, Tobin AB (2000). "Phosphorylation and regulation of a Gq/11-coupled receptor by casein kinase 1alpha.". J. Biol. Chem. 275 (26): 19667–75. doi:10.1074/jbc.M000492200. PMID 10777483. 

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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