Muscarinic acetylcholine receptor M3

Mechanism

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. The calcium function in vertebrates also involves activation of protein kinase C and its effects.

Effects

Smooth muscle

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.

Diabetes

The muscarinic M3 receptor regulates insulin secretion from the pancreas 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.

Other

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:

• increased secretions from stomach
• eye accommodation

Ligands

Agonists

No highly selective M3 agonists are yet available as of 2018, but a number of non-selective muscarinic agonists are active at M3.

• acetylcholine
• bethanechol
• carbachol
• L-689,660 (mixed M1/M3 agonist)
• oxotremorine
• pilocarpine (in eye)
• muscarine

Antagonists

• atropine

• AZD9164

• tramadol

• hyoscyamine

• aclidinium bromide

• 4-DAMP (1,1-Dimethyl-4-diphenylacetoxypiperidinium iodide, CAS# 1952-15-4)

• darifenacin

• diphenhydramine

• fluoxetine

• 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)

• HL-031,120 ((3R,2'R)-enantiomer of EA-3167)

• ipratropium

• J-104,129 ((aR)-a-Cyclopentyl-a-hydroxy-N-[1-(4-methyl-3-pentenyl)-4-piperidinyl]benzeneacetamide, CAS# 244277-89-2)

• oxybutynin

• procyclidine

• tiotropium

• tolterodine

• zamifenacin ((3R)-1-[2-(1-,3-Benzodioxol-5-yl)ethyl]-3-(diphenylmethoxy)piperidine, CAS# 127308-98-9)

• solifenacin

Interactions

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. It has also been shown to interact with Arf6 and ARF1.

References

References

1. (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.
2. (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. "Entrez Gene: CHRM3 cholinergic receptor, muscarinic 3".
4. (August 2011). "Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers". Nature Chemical Biology.
5. (2006). "Goodman & Gilman's the pharmacological basis of therapeutics". McGraw-Hill.
6. (2003). "Pharmacology". Elsevier Churchill Livingstone.
7. (November 2002). "The inhibitory effects of tramadol on muscarinic receptor-induced responses in Xenopus oocytes expressing cloned M(3) receptors". Anesthesia and Analgesia.
8. (May 2010). "DailyMed". U.S. National Library of Medicine.
9. (September 2003). "ADP-ribosylation factor-dependent phospholipase D activation by the M3 muscarinic receptor". The Journal of Biological Chemistry.