Muscarinic acetylcholine receptor M₃

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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.^[1]

The M₃ muscarinic receptors are located at many places in the body, e.g., smooth muscles, 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.^[2] These receptors are highly expressed on pancreatic beta cells and are critical regulators of glucose homoestasis by modulating insulin secretion.^[3] 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.^[4] 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.^[5]

Diabetes

The muscarinic M₃ receptor regulates insulin secretion from the pancreas^[3] 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.^[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 2018, but a number of non-selective muscarinic agonists are active at M3.

acetylcholine
bethanechol
carbachol^[6]
L-689,660 (mixed M1/M3 agonist)
oxotremorine^[6]
pilocarpine (in eye)

Antagonists

atropine^[4]^[6]
hyoscyamine^[7]

aclidinium bromide
4-DAMP (1,1-Dimethyl-4-diphenylacetoxypiperidinium iodide, CAS# 1952-15-4)
darifenacin
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^[6]
HL-031,120 ((3R,2'R)-enantiomer of EA-3167)
ipratropium^[6]
J-104,129 ((aR)-a-Cyclopentyl-a-hydroxy-N-[1-(4-methyl-3-pentenyl)-4-piperidinyl]benzeneacetamide, CAS# 244277-89-2)
oxybutynin^[6]
tiotropium
tolterodine^[6]
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 pre-couple with Gq proteins. The polybasic c-tail of the receptor is necessary for the pre-coupling.^[4] It has also been shown interact with Arf6^[8] and ARF1.^[8]

References

↑ ^1.0 ^1.1 "Entrez Gene: CHRM3 cholinergic receptor, muscarinic 3".
↑ ^2.0 ^2.1 Weston-Green K, Huang XF, Lian J, Deng C (May 2012). "Effects of olanzapine on muscarinic M3 receptor binding density in the brain relates to weight gain, plasma insulin and metabolic hormone levels". European Neuropsychopharmacology. 22 (5): 364–73. doi:10.1016/j.euroneuro.2011.09.003. PMID 21982116.
↑ ^3.0 ^3.1 Gautam D, Han SJ, Hamdan FF, Jeon J, Li B, Li JH, Cui Y, Mears D, Lu H, Deng C, Heard T, Wess J (June 2006). "A critical role for [beta] cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo". Cell Metabolism. 3 (6): 449–461. doi:10.1016/j.cmet.2006.04.009. PMID 16753580.
↑ ^4.0 ^4.1 ^4.2 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.
↑ 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.
↑ ^6.0 ^6.1 ^6.2 ^6.3 ^6.4 ^6.5 ^6.6 Rang HP, Dale MM, Ritter JM, Moore PK (2003). "Ch. 10". Pharmacology (5th ed.). Elsevier Churchill Livingstone. p. 139. ISBN 0-443-07145-4.
↑ Edwards Pharmaceuticals, Inc.; Belcher Pharmaceuticals, Inc. (May 2010), DailyMed, U.S. National Library of Medicine, retrieved January 13, 2013
↑ ^8.0 ^8.1 Mitchell R, Robertson DN, Holland PJ, Collins D, Lutz EM, Johnson MS (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.

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

[entrezM3-1] 1.0 ^1.1 "Entrez Gene: CHRM3 cholinergic receptor, muscarinic 3".

[Weston-Green_2012_364–73-2] 2.0 ^2.1 Weston-Green K, Huang XF, Lian J, Deng C (May 2012). "Effects of olanzapine on muscarinic M3 receptor binding density in the brain relates to weight gain, plasma insulin and metabolic hormone levels". European Neuropsychopharmacology. 22 (5): 364–73. doi:10.1016/j.euroneuro.2011.09.003. PMID 21982116.

[Gautam_2006_449–461-3] 3.0 ^3.1 Gautam D, Han SJ, Hamdan FF, Jeon J, Li B, Li JH, Cui Y, Mears D, Lu H, Deng C, Heard T, Wess J (June 2006). "A critical role for [beta] cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo". Cell Metabolism. 3 (6): 449–461. doi:10.1016/j.cmet.2006.04.009. PMID 16753580.

[Kou_Qin-4] 4.0 ^4.1 ^4.2 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.

[isbn0-07-142280-3-5] 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.

[Rang-6] 6.0 ^6.1 ^6.2 ^6.3 ^6.4 ^6.5 ^6.6 Rang HP, Dale MM, Ritter JM, Moore PK (2003). "Ch. 10". Pharmacology (5th ed.). Elsevier Churchill Livingstone. p. 139. ISBN 0-443-07145-4.

[7] Edwards Pharmaceuticals, Inc.; Belcher Pharmaceuticals, Inc. (May 2010), DailyMed, U.S. National Library of Medicine, retrieved January 13, 2013

[pmid12799371-8] 8.0 ^8.1 Mitchell R, Robertson DN, Holland PJ, Collins D, Lutz EM, Johnson MS (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.

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