Muscarinic_acetylcholine_receptor_M1

Muscarinic acetylcholine receptor M<sub>1</sub>

Muscarinic acetylcholine receptor M1

Protein-coding gene in the species Homo sapiens


The muscarinic acetylcholine receptor M1, also known as the cholinergic receptor, muscarinic 1, is a muscarinic receptor that in humans is encoded by the CHRM1 gene.[5] It is localized to 11q13.[5]

Quick Facts CHRM1, Available structures ...

This receptor is found mediating slow EPSP at the ganglion in the postganglionic nerve,[6] is common in exocrine glands and in the CNS.[7][8]

It is predominantly found bound to G proteins of class Gq[9][10] that use upregulation of phospholipase C and, therefore, inositol trisphosphate and intracellular calcium as a signalling pathway. A receptor so bound would not be susceptible to CTX or PTX. However, Gi (causing a downstream decrease in cAMP) and Gs (causing an increase in cAMP) have also been shown to be involved in interactions in certain tissues, and so would be susceptible to PTX and CTX respectively.

Effects

Occurrence in free living amoebae

A structural but not sequential homolog of the human M1 receptor has been reported in Acanthamoeba castellanii[15] and Naegleria fowleri.[16] Antagonists of human M1 receptors (e.g. atropine, diphenhydramine) have been shown to exert anti-proliferative effects on these pathogens.

Mechanism

It couples to Gq, and, to a small extent, Gi and Gs. This results in slow EPSP and decreased K+ conductance.[12][17] It is preassembled to the Gq heterotrimer through a polybasic c-terminal domain.[9]

Ligands

Agonists

Allosteric modulators

  • benzylquinolone carboxylic acid[19]
  • BQZ-12[20]
  • VU-0090157[21]
  • VU-0029767[21]
  • VU0467319[22]
  • [3H]PT-1284- M1-selective PAM Radioligand[23]

Antagonists

See also


References

  1. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  2. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. Messer WS (20 January 2000). "Acetylcholine". University of Toledo. Archived from the original on 14 October 2007. Retrieved 27 October 2007.
  4. Johnson G (2002). PDQ Pharmacology (2nd ed.). Hamilton, Ontario: BC Decker Inc. pp. 311 pages. ISBN 1-55009-109-3.
  5. Richelson E (1995). "Cholinergic Transduction". In Bloom FE, Kupfer DJ (eds.). Psychopharmacology: the fourth generation of progress: an official publication of the American College of Neuropsychopharmacology (Fourth ed.). New York: Lippincott Williams & Wilkins. ISBN 978-0781701662. Retrieved 27 October 2007.
  6. Qin K, Dong C, Wu G, Lambert NA (August 2011). "Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers". Nature Chemical Biology. 7 (10): 740–747. doi:10.1038/nchembio.642. PMC 3177959. PMID 21873996.
  7. Dawson AH, Buckley NA (March 2016). "Pharmacological management of anticholinergic delirium - theory, evidence and practice". British Journal of Clinical Pharmacology. 81 (3): 516–524. doi:10.1111/bcp.12839. PMC 4767198. PMID 26589572. Delirium is only associated with the antagonism of post‐synaptic M1 receptors and to date other receptor subtypes have not been implicated
  8. Rang HP, Dale MM, Ritter JM, Moore PK (2003). "10". Pharmacology (5th ed.). Elsevier Churchill Livingstone. p. 139. ISBN 0-443-07145-4.
  9. Dawson AH, Buckley NA (March 2016). "Pharmacological management of anticholinergic delirium - theory, evidence and practice". British Journal of Clinical Pharmacology. 81 (3): 516–524. doi:10.1111/bcp.12839. PMC 4767198. PMID 26589572. Delirium is only associated with the antagonism of post‐synaptic M1 receptors and to date other receptor subtypes have not been implicated
  10. Smith RS, Hu R, DeSouza A, Eberly CL, Krahe K, Chan W, et al. (July 2015). "Differential Muscarinic Modulation in the Olfactory Bulb". The Journal of Neuroscience. 35 (30): 10773–10785. doi:10.1523/JNEUROSCI.0099-15.2015. PMC 4518052. PMID 26224860.
  11. Hamilton SE, Loose MD, Qi M, Levey AI, Hille B, McKnight GS, et al. (November 1997). "Disruption of the m1 receptor gene ablates muscarinic receptor-dependent M current regulation and seizure activity in mice". Proceedings of the National Academy of Sciences of the United States of America. 94 (24): 13311–13316. Bibcode:1997PNAS...9413311H. doi:10.1073/pnas.94.24.13311. PMC 24305. PMID 9371842.
  12. Bradley SJ, Bourgognon JM, Sanger HE, Verity N, Mogg AJ, White DJ, et al. (February 2017). "M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss". The Journal of Clinical Investigation. 127 (2): 487–499. doi:10.1172/JCI87526. PMC 5272187. PMID 27991860.
  13. Marlo JE, Niswender CM, Days EL, Bridges TM, Xiang Y, Rodriguez AL, et al. (March 2009). "Discovery and characterization of novel allosteric potentiators of M1 muscarinic receptors reveals multiple modes of activity". Molecular Pharmacology. 75 (3): 577–588. doi:10.1124/mol.108.052886. PMC 2684909. PMID 19047481.
  14. Clinical trial number NCT04051801 for "Multiple Ascending Dose Phase I Study of the M1 Positive Allosteric Modulator VU0467319" at ClinicalTrials.gov
  15. Smith DL, Davoren JE, Edgerton JR, Lazzaro JT, Lee CW, Neal S, et al. (September 2016). "Characterization of a Novel M1 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator Radioligand, [3H]PT-1284". Molecular Pharmacology. 90 (3): 177–187. doi:10.1124/mol.116.104737. PMID 27382013.
  16. Dawson AH, Buckley NA (March 2016). "Pharmacological management of anticholinergic delirium - theory, evidence and practice". British Journal of Clinical Pharmacology. 81 (3): 516–524. doi:10.1111/bcp.12839. PMC 4767198. PMID 26589572. Delirium is only associated with the antagonism of post‐synaptic M1 receptors and to date other receptor subtypes have not been implicated
  17. Hennies HH, Friderichs E, Schneider J (July 1988). "Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids". Arzneimittel-Forschung. 38 (7): 877–880. PMID 2849950.
  18. Edwards Pharmaceuticals, Inc., Belcher Pharmaceuticals, Inc. (May 2010). "DailyMed". U.S. National Library of Medicine. Retrieved 13 January 2013.
  19. Eltze M, Figala V (December 1988). "Affinity and selectivity of biperiden enantiomers for muscarinic receptor subtypes". European Journal of Pharmacology. 158 (1–2): 11–19. doi:10.1016/0014-2999(88)90247-6. PMID 3220113.

Further reading

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


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