Muscarinic acetylcholine receptor M3

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Cholinergic receptor, muscarinic 3
4daj.png
Rat M3 muscarinic acetylcholine receptor/lysozyme fusion protein with bound tiotropium. PDB 4daj[1]
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols CHRM3 ; EGBRS; HM3
External IDs OMIM118494 MGI88398 HomoloGene20191 IUPHAR: M3 ChEMBL: 245 GeneCards: CHRM3 Gene
Orthologs
Species Human Mouse
Entrez 1131 12671
Ensembl ENSG00000133019 ENSMUSG00000046159
UniProt P20309 Q9ERZ3
RefSeq (mRNA) NM_000740 NM_033269
RefSeq (protein) NP_000731 NP_150372
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.[2]

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.[3] These receptors are highly expressed on pancreatic beta cells and are critical regulators of glucose homoestasis by modulating insulin secretion.[4] In general, they cause smooth muscle contraction and increased glandular secretions.[2]

They are unresponsive to PTX and CTX.

Mechanism[edit]

Like the M1 muscarinic receptor, M3 receptors are coupled to G proteins of class Gq, which upregulate phospholipase C and, therefore, inositol trisphosphate and intracellular calcium as a signalling pathway.[5] The calcium function in vertebrates also involves activation of protein kinase C and its effects.

Effects[edit]

Smooth muscle[edit]

Because the M3 receptor is Gq-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.[6]

Diabetes[edit]

The muscarinic M3 receptor regulates insulin secretion from the pancreas[4] 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.[3]

Other[edit]

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:

Agonists[edit]

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

Antagonists[edit]

  • atropine[5][7]
  • Hyoscyamine[8]
  • 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[7]
  • 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[7]
  • oxybutynin[7]
  • ipratropium[7]
  • darifenacin
  • tiotropium
  • Zamifenacin ((3R)-1-[2-(1-,3-Benzodioxol-5-yl)ethyl]-3-(diphenylmethoxy)piperidine, CAS# 127308-98-9)

Interactions[edit]

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.[5] It has also been shown interact with Arf6[9] and ARF1.[9]

See also[edit]

References[edit]

  1. ^ Kruse, A. C.; Hu, J.; Pan, A. C.; Arlow, D. H.; Rosenbaum, D. M.; Rosemond, E.; Green, H. F.; Liu, T.; Chae, P. S.; Dror, R. O.; Shaw, D. E.; Weis, W. I.; Wess, J. R.; Kobilka, B. K. (2012). "Structure and dynamics of the M3 muscarinic acetylcholine receptor". Nature 482 (7386): 552–556. doi:10.1038/nature10867. PMC 3529910. PMID 22358844.  edit
  2. ^ a b "Entrez Gene: CHRM3 cholinergic receptor, muscarinic 3". 
  3. ^ a b 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. 
  4. ^ a b Gautam, D; et al., (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. 
  5. ^ a b c Kou Qin, Chunmin Dong, Guangyu Wu & Nevin A Lambert (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. 
  6. ^ 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. 
  7. ^ 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. 
  8. ^ Edwards Pharmaceuticals, Inc.; Belcher Pharmaceuticals, Inc. (May 2010), DailyMed, U.S. National Library of Medicine, retrieved January 13, 2013 
  9. ^ 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[edit]

Further reading[edit]

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