Muscarinic acetylcholine receptor M3

The muscarinic acetylcholine receptor, also known as cholinergic/acetylcholine receptor M₃, or the muscarinic 3, is a muscarinic acetylcholine receptor encoded by the human gene CHRM3.

The M₃ muscarinic receptors are located at many places in the body, e.g., smooth muscles, the bladder, the endocrine glands, the exocrine glands, lungs, pancreas and the brain. In the CNS, they induce emesis. Muscarinic M₃ receptors are expressed in regions of the brain that regulate insulin homeostasis, such as the hypothalamus and dorsal vagal complex of the brainstem.{{cite journal | vauthors = Weston-Green K, Huang XF, Lian J, Deng C | title = Effects of olanzapine on muscarinic M3 receptor binding density in the brain relates to weight gain, plasma insulin and metabolic hormone levels | journal = European Neuropsychopharmacology | volume = 22 | issue = 5 | pages = 364–373 | date = May 2012 | pmid = 21982116 | doi = 10.1016/j.euroneuro.2011.09.003 | s2cid = 31739607 }} These receptors are highly expressed on pancreatic beta cells and are critical regulators of glucose homoestasis by modulating insulin secretion.{{cite journal | vauthors = Gautam D, Han SJ, Hamdan FF, Jeon J, Li B, Li JH, Cui Y, Mears D, Lu H, Deng C, Heard T, Wess J | display-authors = 6 | title = A critical role for beta cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo | journal = Cell Metabolism | volume = 3 | issue = 6 | pages = 449–461 | date = June 2006 | pmid = 16753580 | doi = 10.1016/j.cmet.2006.04.009 | hdl-access = free | hdl = 10533/177761 }} In general, they cause smooth muscle contraction and increased glandular secretions.{{cite web | title = Entrez Gene: CHRM3 cholinergic receptor, muscarinic 3| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1131}}

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.{{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 = 740–747 | date = August 2011 | pmid = 21873996 | pmc = 3177959 | doi = 10.1038/nchembio.642 }} 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.{{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 = 0-07-142280-3 }}

=Diabetes=

The muscarinic M₃ receptor regulates insulin secretion from the pancreas and are an important target for understanding the mechanisms of type 2 diabetes mellitus.

Some antipsychotic drugs that are prescribed to treat schizophrenia and bipolar disorder (such as olanzapine and clozapine) have a high risk of diabetes side-effects. These drugs potently bind to and block the muscarinic M₃ receptor, which causes insulin dysregulation that may precede diabetes.

=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

Ligands

=Agonists=

No highly selective M3 agonists are yet available as of 2018, but a number of non-selective muscarinic agonists are active at M3.

acetylcholine
bethanechol
carbachol{{cite book |vauthors=Rang HP, Dale MM, Ritter JM, Moore PK | year = 2003| title = Pharmacology | chapter = Ch. 10 | edition = 5th | pages = [https://archive.org/details/clinicalpharmaco00frcp/page/n154 139] | publisher = Elsevier Churchill Livingstone| isbn = 0-443-07145-4| url =https://archive.org/details/clinicalpharmaco00frcp|url-access=limited }}
L-689,660 (mixed M1/M3 agonist)
oxotremorine
pilocarpine (in eye)
muscarine

=Antagonists=

atropine
tramadol{{cite journal | vauthors = Shiga Y, Minami K, Shiraishi M, Uezono Y, Murasaki O, Kaibara M, Shigematsu A | title = The inhibitory effects of tramadol on muscarinic receptor-induced responses in Xenopus oocytes expressing cloned M(3) receptors | journal = Anesthesia and Analgesia | volume = 95 | issue = 5 | pages = 1269–73, table of contents | date = November 2002 | pmid = 12401609 | doi = 10.1097/00000539-200211000-00031 | s2cid = 39621215 | doi-access = free }}
hyoscyamine{{cite web | last1 = Edwards Pharmaceuticals, Inc. | last2 = Belcher Pharmaceuticals, Inc. | title = DailyMed | publisher = U.S. National Library of Medicine | date = May 2010 | url = http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f33a4774-9fbb-4782-a7e1-068e83b7504d | access-date = January 13, 2013}}

aclidinium bromide
4-DAMP (1,1-Dimethyl-4-diphenylacetoxypiperidinium iodide, CAS# 1952-15-4)
darifenacin
diphenhydramine
fluoxetine
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)
HL-031,120 ((3R,2'R)-enantiomer of EA-3167)
ipratropium
J-104,129 ((aR)-a-Cyclopentyl-a-hydroxy-N-[1-(4-methyl-3-pentenyl)-4-piperidinyl]benzeneacetamide, CAS# 244277-89-2)
oxybutynin
procyclidine
tiotropium
tolterodine
zamifenacin ((3R)-1-[2-(1-,3-Benzodioxol-5-yl)ethyl]-3-(diphenylmethoxy)piperidine, CAS# 127308-98-9)
solifenacin

Interactions

Muscarinic acetylcholine receptor M3 has been shown to pre-couple with Gq proteins. The polybasic c-tail of the receptor is necessary for the pre-coupling. It has also been shown to interact with Arf6{{cite journal | vauthors = Mitchell R, Robertson DN, Holland PJ, Collins D, Lutz EM, Johnson MS | title = ADP-ribosylation factor-dependent phospholipase D activation by the M3 muscarinic receptor | journal = The Journal of Biological Chemistry | volume = 278 | issue = 36 | pages = 33818–33830 | date = September 2003 | pmid = 12799371 | doi = 10.1074/jbc.M305825200 | doi-access = free }} and ARF1.

References

External links

{{cite web | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2143 | title = Acetylcholine receptors (muscarinic): M₃ | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | access-date = 2008-11-25 | archive-date = 2013-11-03 | archive-url = https://web.archive.org/web/20131103053707/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2143 | url-status = dead }}
{{PDBe-KB2|P20309|Human Muscarinic acetylcholine receptor M3}}
{{PDBe-KB2|P08483|Rat Muscarinic acetylcholine receptor M3}}

Category:Muscarinic acetylcholine receptors