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Muscarinic acetylcholine receptor M1

Protein-coding gene in the species Homo sapiens

Summary

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. It is localized to 11q13.

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

It is predominantly found bound to G proteins of class Gq 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
  • Via the central nervous system (especially within the brain); mediating certain core aspects of perception, attention, cognitive functioning and likely; memory consolidation. 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.
  • Cognitive flexibility
  • Synaptic plasticity modulation
  • Anxiety-like behavior and spontaneous working memory
  • Task switching
  • Vagally-induced bronchoconstriction
  • Mediating olfactory behaviors and detection of "social odors" which have implications (for rodents) in aggression, mating, and social behavior.

Occurrence in free living amoebae

A structural but not sequential homolog of the human M1 receptor has been reported in Acanthamoeba castellanii and Naegleria fowleri. 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. It is preassembled to the Gq heterotrimer through a polybasic c-terminal domain.

Ligands

Agonists

  • Acetylcholine
  • Arecoline
  • Carbachol
  • Cevimeline
  • Itameline
  • Muscarine
  • Oxotremorine
  • Pilocarpine
  • Vedaclidine
  • Xanomeline
  • 77-LH-28-1 - brain penetrant selective M1 allosteric agonist
  • CDD-0097
  • McN-A-343 - mixed M1/M4 agonist
  • L-689, L-660 - mixed M1/M3 agonist

Allosteric modulators

  • BQCA
  • BQZ-12
  • VU-0090157
  • VU-0029767
  • VU0467319
  • [3H]PT-1284- M1-selective PAM Radioligand

Antagonists

  • atropine
  • diphenhydramine
  • scopolamine
  • tramadol
  • dicycloverine
  • fluoxetine
  • hyoscyamine
  • ipratropium
  • mamba toxin muscarinic toxin 7 (MT7)
  • Many antipsychotics like olanzapine, quetiapine, clozapine, chlorpromazine
  • pirenzepine
  • oxybutynin
  • Benzatropine
  • telenzepine
  • paroxetine
  • PIPE-359
  • Tricyclic and tetracyclic antidepressants like clomipramine, imipramine, mirtazapine, amitriptyline
  • tolterodine
  • Biperiden

References

References

  1. "Entrez Gene: CHRM1 cholinergic receptor, muscarinic 1".
  2. (2000-01-20). "Acetylcholine". University of Toledo.
  3. (2002). "PDQ Pharmacology". BC Decker Inc.
  4. (1995). "Psychopharmacology: the fourth generation of progress: an official publication of the American College of Neuropsychopharmacology". Lippincott Williams & Wilkins.
  5. (August 2011). "Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers". Nature Chemical Biology.
  6. (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.
  7. (March 2016). "Pharmacological management of anticholinergic delirium - theory, evidence and practice". British Journal of Clinical Pharmacology.
  8. (March 2016). "Pharmacological management of anticholinergic delirium - theory, evidence and practice". British Journal of Clinical Pharmacology.
  9. (July 2015). "Differential Muscarinic Modulation in the Olfactory Bulb". The Journal of Neuroscience.
  10. (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.
  11. (August 2016). "Primary Amoebic Meningoencephalitis: Neurochemotaxis and Neurotropic Preferences of Naegleria fowleri". ACS Chemical Neuroscience.
  12. (October 2022). "Muscarine reduces inwardly rectifying potassium conductance in rat nucleus accumbens neurones". The Journal of Physiology.
  13. (2003). "Pharmacology". Elsevier Churchill Livingstone.
  14. (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.
  15. (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.
  16. (February 2017). "M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss". The Journal of Clinical Investigation.
  17. (March 2009). "Discovery and characterization of novel allosteric potentiators of M1 muscarinic receptors reveals multiple modes of activity". Molecular Pharmacology.
  18. {{ClinicalTrialsGov. NCT04051801. Multiple Ascending Dose Phase I Study of the M1 Positive Allosteric Modulator VU0467319
  19. (September 2016). "Characterization of a Novel M1 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator Radioligand, [3H]PT-1284". Molecular Pharmacology.
  20. (March 2016). "Pharmacological management of anticholinergic delirium - theory, evidence and practice". British Journal of Clinical Pharmacology.
  21. (July 1988). "Receptor binding, analgesic and antitussive potency of tramadol and other selected opioids". Arzneimittel-Forschung.
  22. (May 2010). "ED-SPAZ- hyoscyamine sulfate tablet, orally disintegrating". U.S. National Library of Medicine.
  23. (December 1988). "Affinity and selectivity of biperiden enantiomers for muscarinic receptor subtypes". European Journal of Pharmacology.
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