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]
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
- EPSP in autonomic ganglia
- Secretion from salivary glands
- Gastric acid secretion from stomach[5]
- Via the central nervous system (especially within the brain); mediating certain core aspects of perception, attention, cognitive functioning and likely; memory consolidation.[11][12] 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.[13]
- Cognitive flexibility
- Synaptic plasticity modulation
- Anxiety-like behavior and spontaneous working memory
- Salivation
- Task switching
- Vagally-induced bronchoconstriction[5]
- Mediating olfactory behaviors and detection of “social odors” which have implications (for rodents) in aggression, mating, and social behavior.[14]
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
- acetylcholine
- carbachol[12]
- cevimeline
- muscarine
- oxotremorine
- pilocarpine[18]
- vedaclidine
- xanomeline
- 77-LH-28-1 - brain penetrant selective M1 allosteric agonist
- CDD-0097
- McN-A-343 - mixed M1/M4 agonist[12]
- L-689, L-660 - mixed M1/M3 agonist
Allosteric modulators
Antagonists
- atropine[12]
- diphenhydramine
- scopolamine[24]
- tramadol[25]
- dicycloverine[12]
- fluoxetine
- hyoscyamine[26]
- ipratropium[12]
- mamba toxin muscarinic toxin 7 (MT7)[12]
- Many antipsychotics like olanzapine, quetiapine, clozapine, chlorpromazine
- pirenzepine
- oxybutynin[12]
- Benzatropine
- telenzepine
- paroxetine
- Tricyclic and tetracyclic antidepressants like clomipramine, imipramine, mirtazapine, amitriptyline
- tolterodine[12]
- Biperiden[27]
See also
References
- 1 2 3 GRCh38: Ensembl release 89: ENSG00000168539 - Ensembl, May 2017
- 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000032773 - Ensembl, May 2017
- ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- 1 2 3 4 "Entrez Gene: CHRM1 cholinergic receptor, muscarinic 1".
- ↑ Messer WS (20 January 2000). "Acetylcholine". University of Toledo. Archived from the original on 14 October 2007. Retrieved 27 October 2007.
- ↑ Johnson G (2002). PDQ Pharmacology (2nd ed.). Hamilton, Ontario: BC Decker Inc. pp. 311 pages. ISBN 1-55009-109-3.
{{cite book}}: CS1 maint: overridden setting (link) - ↑ 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.
{{cite book}}: CS1 maint: overridden setting (link) - 1 2 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.
- ↑ Burford NT, Nahorski SR (May 1996). "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. doi:10.1042/bj3150883. PMC 1217289. PMID 8645172.
- ↑ 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
- 1 2 3 4 5 6 7 8 9 10 Rang HP, Dale MM, Ritter JM, Moore PK (2003). "10". Pharmacology (5th ed.). Elsevier Churchill Livingstone. p. 139. ISBN 0-443-07145-4.
- ↑ 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
- ↑ Smith RS, Hu R, DeSouza A, Eberly CL, Krahe K, Chan W, Araneda RC (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.
- ↑ Baig AM, Ahmad HR (June 2017). "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. doi:10.1080/10799893.2016.1217884. PMID 27601178. S2CID 5234123.
- ↑ Baig AM (August 2016). "Primary Amoebic Meningoencephalitis: Neurochemotaxis and Neurotropic Preferences of Naegleria fowleri". ACS Chemical Neuroscience. 7 (8): 1026–1029. doi:10.1021/acschemneuro.6b00197. PMID 27447543.
- ↑ Uchimura N, North RA (March 1990). "Muscarine reduces inwardly rectifying potassium conductance in rat nucleus accumbens neurones". The Journal of Physiology. 422 (1): 369–380. doi:10.1113/jphysiol.1990.sp017989. PMC 1190137. PMID 1693682.
- ↑ 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.
- ↑ Shirey JK, Brady AE, Jones PJ, Davis AA, Bridges TM, Kennedy JP, et al. (November 2009). "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. doi:10.1523/JNEUROSCI.3930-09.2009. PMC 2811323. PMID 19906975.
- ↑ 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.
- 1 2 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.
- ↑ Clinical trial number NCT04051801 for "Multiple Ascending Dose Phase I Study of the M1 Positive Allosteric Modulator VU0467319" at ClinicalTrials.gov
- ↑ 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.
- ↑ 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
- ↑ 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.
- ↑ Edwards Pharmaceuticals, Inc., Belcher Pharmaceuticals, Inc. (May 2010). "DailyMed". U.S. National Library of Medicine. Retrieved 13 January 2013.
- ↑ 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
- Goyal RK (October 1989). "Muscarinic receptor subtypes. Physiology and clinical implications". The New England Journal of Medicine. 321 (15): 1022–1029. doi:10.1056/NEJM198910123211506. PMID 2674717.
- Brann MR, Ellis J, Jørgensen H, Hill-Eubanks D, Jones SV (1993). "Chapter 12: Muscarinic acetylcholine receptor subtypes: Localization and structure/Function". Cholinergic Function and Dysfunction. Progress in Brain Research. Vol. 98. pp. 121–7. doi:10.1016/S0079-6123(08)62388-2. ISBN 9780444897176. PMID 8248499.
- Nitsch RM, Slack BE, Wurtman RJ, Growdon JH (October 1992). "Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors". Science. 258 (5080): 304–307. Bibcode:1992Sci...258..304N. doi:10.1126/science.1411529. PMID 1411529.
- Arden JR, Nagata O, Shockley MS, Philip M, Lameh J, Sadée W (November 1992). "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. doi:10.1016/0006-291X(92)91346-R. PMID 1445347.
- Gutkind JS, Novotny EA, Brann MR, Robbins KC (June 1991). "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. Bibcode:1991PNAS...88.4703G. doi:10.1073/pnas.88.11.4703. PMC 51734. PMID 1905013.
- Chapman CG, Browne MJ (April 1990). "Isolation of the human ml (Hml) muscarinic acetylcholine receptor gene by PCR amplification". Nucleic Acids Research. 18 (8): 2191. doi:10.1093/nar/18.8.2191. PMC 330717. PMID 2336407.
- Ashkenazi A, Ramachandran J, Capon DJ (July 1989). "Acetylcholine analogue stimulates DNA synthesis in brain-derived cells via specific muscarinic receptor subtypes". Nature. 340 (6229): 146–150. Bibcode:1989Natur.340..146A. doi:10.1038/340146a0. PMID 2739737. S2CID 4312544.
- Bonner TI, Buckley NJ, Young AC, Brann MR (July 1987). "Identification of a family of muscarinic acetylcholine receptor genes". Science. 237 (4814): 527–532. Bibcode:1987Sci...237..527B. doi:10.1126/science.3037705. PMID 3037705.
- Peralta EG, Ashkenazi A, Winslow JW, Smith DH, Ramachandran J, Capon DJ (December 1987). "Distinct primary structures, ligand-binding properties and tissue-specific expression of four human muscarinic acetylcholine receptors". The EMBO Journal. 6 (13): 3923–3929. doi:10.1002/j.1460-2075.1987.tb02733.x. PMC 553870. PMID 3443095.
- Allard WJ, Sigal IS, Dixon RA (December 1987). "Sequence of the gene encoding the human M1 muscarinic acetylcholine receptor". Nucleic Acids Research. 15 (24): 10604. doi:10.1093/nar/15.24.10604. PMC 339984. PMID 3697105.
- Svoboda P, Milligan G (September 1994). "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. doi:10.1111/j.1432-1033.1994.00455.x. PMID 7925360.
- Crespo P, Xu N, Daniotti JL, Troppmair J, Rapp UR, Gutkind JS (August 1994). "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. doi:10.1016/S0021-9258(17)31935-X. PMID 8063729.
- Russell M, Winitz S, Johnson GL (April 1994). "Acetylcholine muscarinic m1 receptor regulation of cyclic AMP synthesis controls growth factor stimulation of Raf activity". Molecular and Cellular Biology. 14 (4): 2343–2351. doi:10.1128/mcb.14.4.2343. PMC 358601. PMID 8139539.
- Offermanns S, Wieland T, Homann D, Sandmann J, Bombien E, Spicher K, et al. (May 1994). "Transfected muscarinic acetylcholine receptors selectively couple to Gi-type G proteins and Gq/11". Molecular Pharmacology. 45 (5): 890–898. PMID 8190105.
- Mullaney I, Mitchell FM, McCallum JF, Buckley NJ, Milligan G (June 1993). "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. doi:10.1016/0014-5793(93)81401-K. PMID 8508928. S2CID 84364768.
- Courseaux A, Grosgeorge J, Gaudray P, Pannett AA, Forbes SA, Williamson C, et al. (November 1996). "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. doi:10.1006/geno.1996.0570. PMID 8938448.
- Ishiyama A, López I, Wackym PA (September 1997). "Molecular characterization of muscarinic receptors in the human vestibular periphery. Implications for pharmacotherapy". The American Journal of Otology. 18 (5): 648–654. PMID 9303164.
- Ishizaka N, Noda M, Yokoyama S, Kawasaki K, Yamamoto M, Higashida H (March 1998). "Muscarinic acetylcholine receptor subtypes in the human iris". Brain Research. 787 (2): 344–347. doi:10.1016/S0006-8993(97)01554-0. PMID 9518684. S2CID 22664866.
External links
- "Acetylcholine receptors (muscarinic): M1". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
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