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 cholinergic/acetylcholine receptor M3, also known as the 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, Han SJ, Hamdan FF, Jeon J, Li B, Li JH 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 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. 
  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 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. 

Further reading[edit]

  • Goyal RK, Underhill LH, Goyal RK (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, Hill-Eubanks D, Jones SV (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.  Vancouver style error (help)
  • 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. 
  • 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, Smith DH, Ramachandran J, Capon DJ (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. 
  • 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, Troppmair J, Rapp UR, Gutkind JS (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, Kikkawa U, Shiozaki K, Uchiyama H (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, Enderich J, Wegner M, Nitsch RM (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, Nguyen VT, Zia S, Rodriguez JG 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, Piggott MA, Perry RH, Ince P 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, Yamada S, Ando T, Kazuko F 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. 

External links[edit]

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