Muscarinic acetylcholine receptor M1 explained

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.^[1] It is localized to 11q13.^[1]

This receptor is found mediating slow EPSP at the ganglion in the postganglionic nerve,^[2] is common in exocrine glands and in the CNS.^{[3] [4]}

It is predominantly found bound to G proteins of class G_q^{[5] [6]} 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, G_i (causing a downstream decrease in cAMP) and G_s (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

• EPSP in autonomic ganglia
• Secretion from salivary glands
• Gastric acid secretion from stomach^[1]
• Via the central nervous system (especially within the brain); mediating certain core aspects of perception, attention, cognitive functioning and likely; memory consolidation.^[7] This is a notable component in regards to the M₁ receptor since it helps explain how pharmacological compounds which antagonize the receptor site can consistently produce mental states like delirium (a major disruption in attention and decrease in baseline-level cognitive functioning), as well as the perceptual alterations and conspicuous hallucinations experienced with deliriant drugs like Datura. As of 2015, the M₁ receptor remains the only known muscarinic receptor to have this effect of hallucinogenic delirium when its functionality is inhibited or antagonized.^[8]
• Cognitive flexibility
• Synaptic plasticity modulation
• Anxiety-like behavior and spontaneous working memory
• Salivation
• Task switching
• Vagally-induced bronchoconstriction^[1]
• Mediating olfactory behaviors and detection of "social odors" which have implications (for rodents) in aggression, mating, and social behavior.^[9]

Occurrence in free living amoebae

A structural but not sequential homolog of the human M1 receptor has been reported in Acanthamoeba castellanii^[10] and Naegleria fowleri.^[11] Antagonists of human M1 receptors (e.g. atropine, diphenhydramine) have been shown to exert anti-proliferative effects on these pathogens.

Mechanism

It couples to G_q, and, to a small extent, G_i and G_s. This results in slow EPSP and decreased K⁺ conductance.^[12] It is preassembled to the G_q heterotrimer through a polybasic c-terminal domain.^[5]

Ligands

Agonists

• acetylcholine
• carbachol^[13]
• cevimeline
• muscarine
• oxotremorine
• pilocarpine^[14]
• vedaclidine
• xanomeline
• 77-LH-28-1 - brain penetrant selective M₁ allosteric agonist
• CDD-0097
• McN-A-343 - mixed M1/M4 agonist^[13]
• L-689, L-660 - mixed M1/M3 agonist

Allosteric modulators

• benzylquinolone carboxylic acid^[15]
• BQZ-12^[16]
• VU-0090157^[17]
• VU-0029767^[17]
• VU0467319
• [³H]PT-1284- M1-selective PAM Radioligand^[18]

Antagonists

• atropine^[13]
• diphenhydramine
• scopolamine^[19]
• tramadol^[20]
• dicycloverine^[13]
• fluoxetine
• hyoscyamine^[21]
• ipratropium^[13]
• mamba toxin muscarinic toxin 7 (MT7)^[13]
• Many antipsychotics like olanzapine, quetiapine, clozapine, chlorpromazine
• pirenzepine
• oxybutynin^[13]
• Benzatropine
• telenzepine
• paroxetine
• Tricyclic and tetracyclic antidepressants like clomipramine, imipramine, mirtazapine, amitriptyline
• tolterodine^[13]
• Biperiden^[22]

See also

• Muscarinic acetylcholine receptor

Further reading

• Goyal RK . Muscarinic receptor subtypes. Physiology and clinical implications . The New England Journal of Medicine . 321 . 15 . 1022–1029 . October 1989 . 2674717 . 10.1056/NEJM198910123211506 .
• Book: Brann MR, Ellis J, Jørgensen H, Hill-Eubanks D, Jones SV . Chapter 12: Muscarinic acetylcholine receptor subtypes: Localization and structure/Function . Cholinergic Function and Dysfunction . Progress in Brain Research . 1993 . 98 . 121–7 . 8248499 . 10.1016/S0079-6123(08)62388-2 . 9780444897176 .
• Nitsch RM, Slack BE, Wurtman RJ, Growdon JH . Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors . Science . 258 . 5080 . 304–307 . October 1992 . 1411529 . 10.1126/science.1411529 . 1992Sci...258..304N .
• Arden JR, Nagata O, Shockley MS, Philip M, Lameh J, Sadée W . Mutational analysis of third cytoplasmic loop domains in G-protein coupling of the HM1 muscarinic receptor . Biochemical and Biophysical Research Communications . 188 . 3 . 1111–1115 . November 1992 . 1445347 . 10.1016/0006-291X(92)91346-R .
• Gutkind JS, Novotny EA, Brann MR, Robbins KC . Muscarinic acetylcholine receptor subtypes as agonist-dependent oncogenes . Proceedings of the National Academy of Sciences of the United States of America . 88 . 11 . 4703–4707 . June 1991 . 1905013 . 51734 . 10.1073/pnas.88.11.4703 . free . 1991PNAS...88.4703G .
• Chapman CG, Browne MJ . Isolation of the human ml (Hml) muscarinic acetylcholine receptor gene by PCR amplification . Nucleic Acids Research . 18 . 8 . 2191 . April 1990 . 2336407 . 330717 . 10.1093/nar/18.8.2191 .
• Ashkenazi A, Ramachandran J, Capon DJ . Acetylcholine analogue stimulates DNA synthesis in brain-derived cells via specific muscarinic receptor subtypes . Nature . 340 . 6229 . 146–150 . July 1989 . 2739737 . 10.1038/340146a0 . 4312544 . 1989Natur.340..146A .
• Bonner TI, Buckley NJ, Young AC, Brann MR . Identification of a family of muscarinic acetylcholine receptor genes . Science . 237 . 4814 . 527–532 . July 1987 . 3037705 . 10.1126/science.3037705 . 1987Sci...237..527B .
• Peralta EG, Ashkenazi A, Winslow JW, Smith DH, Ramachandran J, Capon DJ . Distinct primary structures, ligand-binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors . The EMBO Journal . 6 . 13 . 3923–3929 . December 1987 . 3443095 . 553870 . 10.1002/j.1460-2075.1987.tb02733.x .
• Allard WJ, Sigal IS, Dixon RA . Sequence of the gene encoding the human M1 muscarinic acetylcholine receptor . Nucleic Acids Research . 15 . 24 . 10604 . December 1987 . 3697105 . 339984 . 10.1093/nar/15.24.10604 .
• Svoboda P, Milligan G . Agonist-induced transfer of the alpha subunits of the guanine-nucleotide-binding regulatory proteins Gq and G11 and of muscarinic m1 acetylcholine receptors from plasma membranes to a light-vesicular membrane fraction . European Journal of Biochemistry . 224 . 2 . 455–462 . September 1994 . 7925360 . 10.1111/j.1432-1033.1994.00455.x . free .
• Crespo P, Xu N, Daniotti JL, Troppmair J, Rapp UR, Gutkind JS . Signaling through transforming G protein-coupled receptors in NIH 3T3 cells involves c-Raf activation. Evidence for a protein kinase C-independent pathway . The Journal of Biological Chemistry . 269 . 33 . 21103–21109 . August 1994 . 8063729 . 10.1016/S0021-9258(17)31935-X . free .
• Russell M, Winitz S, Johnson GL . Acetylcholine muscarinic m1 receptor regulation of cyclic AMP synthesis controls growth factor stimulation of Raf activity . Molecular and Cellular Biology . 14 . 4 . 2343–2351 . April 1994 . 8139539 . 358601 . 10.1128/mcb.14.4.2343 .
• Offermanns S, Wieland T, Homann D, Sandmann J, Bombien E, Spicher K, Schultz G, Jakobs KH . Transfected muscarinic acetylcholine receptors selectively couple to Gi-type G proteins and Gq/11 . Molecular Pharmacology . 45 . 5 . 890–898 . May 1994 . 8190105 .
• Mullaney I, Mitchell FM, McCallum JF, Buckley NJ, Milligan G . The human muscarinic M1 acetylcholine receptor, when express in CHO cells, activates and downregulates both Gq alpha and G11 alpha equally and non-selectively . FEBS Letters . 324 . 2 . 241–245 . June 1993 . 8508928 . 10.1016/0014-5793(93)81401-K . 84364768 . free .
• Courseaux A, Grosgeorge J, Gaudray P, Pannett AA, Forbes SA, Williamson C, Bassett D, Thakker RV, Teh BT, Farnebo F, Shepherd J, Skogseid B, Larsson C, Giraud S, Zhang CX, Salandre J, Calender A . Definition of the minimal MEN1 candidate area based on a 5-Mb integrated map of proximal 11q13. The European Consortium on Men1, (GENEM 1; Groupe d'Etude des Néoplasies Endocriniennes Multiples de type 1) . Genomics . 37 . 3 . 354–365 . November 1996 . 8938448 . 10.1006/geno.1996.0570 .
• Ishiyama A, López I, Wackym PA . Molecular characterization of muscarinic receptors in the human vestibular periphery. Implications for pharmacotherapy . The American Journal of Otology . 18 . 5 . 648–654 . September 1997 . 9303164 .
• Ishizaka N, Noda M, Yokoyama S, Kawasaki K, Yamamoto M, Higashida H . Muscarinic acetylcholine receptor subtypes in the human iris . Brain Research . 787 . 2 . 344–347 . March 1998 . 9518684 . 10.1016/S0006-8993(97)01554-0 . 22664866 .

External links

• Web site: Acetylcholine receptors (muscarinic): M₁ . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology . 25 November 2008 . 2 January 2015 . https://web.archive.org/web/20150102110245/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2139 . dead .

Notes and References

1. Web site: Entrez Gene: CHRM1 cholinergic receptor, muscarinic 1.
2. Web site: Acetylcholine . 2007-10-27 . Messer WS . 2000-01-20 . University of Toledo . dead . https://web.archive.org/web/20071014020222/http://www.neurosci.pharm.utoledo.edu/MBC3320/acetylcholine.htm . 14 October 2007 .
3. Book: Johnson G . PDQ Pharmacology . BC Decker Inc . Hamilton, Ontario . 2002 . 2nd . 311 pages . 1-55009-109-3 .
4. Book: Bloom FE, Kupfer DJ . Psychopharmacology: the fourth generation of progress: an official publication of the American College of Neuropsychopharmacology . Richelson E . Cholinergic Transduction . http://www.acnp.org/g4/GN401000011/Default.htm . 2007-10-27 . 1995 . Lippincott Williams & Wilkins . New York . 978-0781701662 . Fourth .
5. Qin K, Dong C, Wu G, Lambert NA . Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers . Nature Chemical Biology . 7 . 10 . 740–747 . August 2011 . 21873996 . 3177959 . 10.1038/nchembio.642 .
6. Burford NT, Nahorski SR . Muscarinic m1 receptor-stimulated adenylate cyclase activity in Chinese hamster ovary cells is mediated by Gs alpha and is not a consequence of phosphoinositidase C activation . The Biochemical Journal . 315 . Pt 3 . 883–888 . May 1996 . 8645172 . 1217289 . 10.1042/bj3150883 .
7. Dawson AH, Buckley NA . Pharmacological management of anticholinergic delirium - theory, evidence and practice . British Journal of Clinical Pharmacology . 81 . 3 . 516–524 . March 2016 . 26589572 . 4767198 . 10.1111/bcp.12839 . Delirium is only associated with the antagonism of post‐synaptic M1 receptors and to date other receptor subtypes have not been implicated .
8. Dawson AH, Buckley NA . Pharmacological management of anticholinergic delirium - theory, evidence and practice . British Journal of Clinical Pharmacology . 81 . 3 . 516–524 . March 2016 . 26589572 . 4767198 . 10.1111/bcp.12839 . Delirium is only associated with the antagonism of post‐synaptic M1 receptors and to date other receptor subtypes have not been implicated .
9. Smith RS, Hu R, DeSouza A, Eberly CL, Krahe K, Chan W, Araneda RC . Differential Muscarinic Modulation in the Olfactory Bulb . The Journal of Neuroscience . 35 . 30 . 10773–10785 . July 2015 . 26224860 . 4518052 . 10.1523/JNEUROSCI.0099-15.2015 .
10. Baig AM, Ahmad HR . Evidence of a M₁-muscarinic GPCR homolog in unicellular eukaryotes: featuring Acanthamoeba spp bioinformatics 3D-modelling and experimentations . Journal of Receptor and Signal Transduction Research . 37 . 3 . 267–275 . June 2017 . 27601178 . 10.1080/10799893.2016.1217884 . 5234123 .
11. Baig AM . Primary Amoebic Meningoencephalitis: Neurochemotaxis and Neurotropic Preferences of Naegleria fowleri . ACS Chemical Neuroscience . 7 . 8 . 1026–1029 . August 2016 . 27447543 . 10.1021/acschemneuro.6b00197 . free .
12. Uchimura N, North RA . Muscarine reduces inwardly rectifying potassium conductance in rat nucleus accumbens neurones . The Journal of Physiology . 422 . 1 . 369–380 . March 1990 . 1693682 . 1190137 . 10.1113/jphysiol.1990.sp017989 .
13. Book: Rang HP, Dale MM, Ritter JM, Moore PK . 2003 . Pharmacology . limited . 10 . 5th . 139 . Elsevier Churchill Livingstone . 0-443-07145-4.
14. Hamilton SE, Loose MD, Qi M, Levey AI, Hille B, McKnight GS, Idzerda RL, Nathanson NM . 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 . November 1997 . 9371842 . 24305 . 10.1073/pnas.94.24.13311 . free . 1997PNAS...9413311H .
15. Shirey JK, Brady AE, Jones PJ, Davis AA, Bridges TM, Kennedy JP, Jadhav SB, Menon UN, Xiang Z, Watson ML, Christian EP, Doherty JJ, Quirk MC, Snyder DH, Lah JJ, Levey AI, Nicolle MM, Lindsley CW, Conn PJ . A selective allosteric potentiator of the M1 muscarinic acetylcholine receptor increases activity of medial prefrontal cortical neurons and restores impairments in reversal learning . The Journal of Neuroscience . 29 . 45 . 14271–14286 . November 2009 . 19906975 . 2811323 . 10.1523/JNEUROSCI.3930-09.2009 .
16. Bradley SJ, Bourgognon JM, Sanger HE, Verity N, Mogg AJ, White DJ, Butcher AJ, Moreno JA, Molloy C, Macedo-Hatch T, Edwards JM, Wess J, Pawlak R, Read DJ, Sexton PM, Broad LM, Steinert JR, Mallucci GR, Christopoulos A, Felder CC, Tobin AB . M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss . The Journal of Clinical Investigation . 127 . 2 . 487–499 . February 2017 . 27991860 . 5272187 . 10.1172/JCI87526 .
17. Marlo JE, Niswender CM, Days EL, Bridges TM, Xiang Y, Rodriguez AL, Shirey JK, Brady AE, Nalywajko T, Luo Q, Austin CA, Williams MB, Kim K, Williams R, Orton D, Brown HA, Lindsley CW, Weaver CD, Conn PJ . Discovery and characterization of novel allosteric potentiators of M1 muscarinic receptors reveals multiple modes of activity . Molecular Pharmacology . 75 . 3 . 577–588 . March 2009 . 19047481 . 2684909 . 10.1124/mol.108.052886 .
18. Smith DL, Davoren JE, Edgerton JR, Lazzaro JT, Lee CW, Neal S, Zhang L, Grimwood S . Characterization of a Novel M1 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator Radioligand, [3H]PT-1284 . Molecular Pharmacology . 90 . 3 . 177–187 . September 2016 . 27382013 . 10.1124/mol.116.104737 . free .
19. Dawson AH, Buckley NA . Pharmacological management of anticholinergic delirium - theory, evidence and practice . British Journal of Clinical Pharmacology . 81 . 3 . 516–524 . March 2016 . 26589572 . 4767198 . 10.1111/bcp.12839 . Delirium is only associated with the antagonism of post‐synaptic M1 receptors and to date other receptor subtypes have not been implicated .
20. Hennies HH, Friderichs E, Schneider J . Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids . Arzneimittel-Forschung . 38 . 7 . 877–880 . July 1988 . 2849950 .
21. Web site: Edwards Pharmaceuticals, Inc. . Belcher Pharmaceuticals, Inc. . ED-SPAZ- hyoscyamine sulfate tablet, orally disintegrating . DailyMed . U.S. National Library of Medicine . May 2010 . 13 January 2013.
22. Eltze M, Figala V . Affinity and selectivity of biperiden enantiomers for muscarinic receptor subtypes . European Journal of Pharmacology . 158 . 1–2 . 11–19 . December 1988 . 3220113 . 10.1016/0014-2999(88)90247-6 .