Muscarinic acetylcholine receptor M3
Encyclopedia
The muscarinic acetylcholine receptor M3, also known as the cholinergic receptor, muscarinic 3, is a muscarinic acetylcholine receptor
. It is encoded by the human gene CHRM3.
The M3 muscarinic receptors are located at many places in the body, e.g., smooth muscles, the endocrine glands, the exocrine glands, as well as the lungs. They are also found in the CNS
, where they induce emesis. In general, they cause smooth muscle contraction and increased glandular secretions.
They are unresponsive to PTX
and CTX
.
, 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.
-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.
s, and help to stimulate secretion in salivary glands and other glands of the body.
Other effects are:
with Arf6
and ARF1
.
Muscarinic acetylcholine receptor
Muscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons and other cells...
. It is encoded by the human gene CHRM3.
The M3 muscarinic receptors are located at many places in the body, e.g., smooth muscles, the endocrine glands, the exocrine glands, as well as the lungs. They are also found in the CNS
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
, where they induce emesis. In general, they cause smooth muscle contraction and increased glandular secretions.
They are unresponsive to PTX
Pertussis toxin
Pertussis toxin is a protein-based AB5-type exotoxin produced by the bacterium Bordetella pertussis, which causes whooping cough. PT is involved in the colonization of the respiratory tract and the establishment of infection...
and CTX
Cholera toxin
Cholera toxin is a protein complex secreted by the bacterium Vibrio cholerae. CTX is responsible for the massive, watery diarrhea characteristic of cholera infection.- Structure :...
.
Mechanism
Like the M1 muscarinic receptor, M3 receptors are coupled to G proteins of class GqGq alpha subunit
Gq protein or Gq/11 is a heterotrimeric G protein subunit that activates phospholipase C . PLC in turn hydrolyzes Phosphatidylinositol 4,5-bisphosphate to diacyl glycerol and inositol triphosphate signal transduction pathway...
, which upregulate phospholipase C
Phospholipase C
Phosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
and, therefore, inositol trisphosphate and intracellular calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
as a signalling pathway. The calcium function in vertebrates also involves activation of protein kinase C
Protein kinase C
Protein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
and its effects.
Smooth muscle
Because the M3 receptor is GqGq alpha subunit
Gq protein or Gq/11 is a heterotrimeric G protein subunit that activates phospholipase C . PLC in turn hydrolyzes Phosphatidylinositol 4,5-bisphosphate to diacyl glycerol and inositol triphosphate signal transduction pathway...
-coupled and mediates an increase in intracellular calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
, it typically causes constriction of smooth muscle, such as that observed during bronchoconstriction
Bronchoconstriction
Bronchoconstriction is the constriction of the airways in the lungs due to the tightening of surrounding smooth muscle, with consequent coughing, wheezing, and shortness of breath. Bronchoconstriction can also be due to an accumulation of thick mucus....
. However, with respect to vasculature, activation of M3 on vascular endothelial cells causes increased synthesis of nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
, which diffuses to adjacent vascular smooth muscle cells and causes their relaxation and vasodilation
Vasodilation
Vasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When...
, thereby explaining the paradoxical effect of parasympathomimetics on vascular tone and bronchiolar tone. Indeed, direct stimulation of vascular smooth muscle M3 mediates vasoconstriction
Vasoconstriction
Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, particularly the large arteries, small arterioles and veins. The process is the opposite of vasodilation, the widening of blood vessels. The process is particularly important in...
in pathologies wherein the vascular endothelium is disrupted.
Other
The M3 receptors are also located in many glands, both endocrine and exocrine glandExocrine gland
Exocrine glands are a type of ductal glands that secrete their products into ducts that lead directly into the external environment...
s, and help to stimulate secretion in salivary glands and other glands of the body.
Other effects are:
- increased secretions from stomachStomachThe stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...
- Eye accommodationAccommodation (eye)Accommodation is the process by which the vertebrate eye changes optical power to maintain a clear image on an object as its distance changes....
Agonists
No highly selective M3 agonists are yet available as of 2009, but a number of non-selective muscarinic agonists are active at M3.- acetylcholineAcetylcholineThe chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
- bethanecholBethanecholBethanechol is a parasympathomimetic choline carbamate that selectively stimulates muscarinic receptors without any effect on nicotinic receptors. Unlike acetylcholine, bethanechol is not hydrolyzed by cholinesterase and will therefore have a long duration of action. Bethanechol does not involve...
- carbacholCarbacholCarbachol , also known as carbamylcholine, is a drug that binds and activates the acetylcholine receptor. Thus it is classified as a cholinergic agonist. It is primarily used for various ophthalmic purposes, such as for treating glaucoma, or for use during ophthalmic surgery...
- L-689,660 (mixed M1/M3 agonist)
- oxotremorineOxotremorineOxotremorine is a cholinomimetic that acts as a non-selective muscarinic acetylcholine receptor agonist.Oxotremorine produces ataxia, tremor and spasticity, similar to those symptoms seen in Parkinsonism, and has thus become a research tool in experimental studies aimed at determining more...
- pilocarpinePilocarpinePilocarpine is a parasympathomimetic alkaloid obtained from the leaves of tropical American shrubs from the genus Pilocarpus. It is a non-selective muscarinic receptor agonist in the parasympathetic nervous system, which acts therapeutically at the muscarinic acetylcholine receptor M3 due to its...
(in eye)
Antagonists
- atropineAtropineAtropine is a naturally occurring tropane alkaloid extracted from deadly nightshade , Jimson weed , mandrake and other plants of the family Solanaceae. It is a secondary metabolite of these plants and serves as a drug with a wide variety of effects...
- 4-DAMP (1,1-Dimethyl-4-diphenylacetoxypiperidinium iodide, CAS# 1952-15-4)
- 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)
- dicycloverine
- J-104,129 ((aR)-a-Cyclopentyl-a-hydroxy-N-[1-(4-methyl-3-pentenyl)-4-piperidinyl]benzeneacetamide, CAS# 244277-89-2)
- HL-031,120 ((3R,2'R)-enantiomer of EA-3167EA-3167EA-3167 is a potent and long lasting anticholinergic deliriant drug, related to the chemical warfare agent 3-Quinuclidinyl benzilate . It was developed under contract to Edgewood Arsenal during the 1960s as part of the US military chemical weapons program, in an attempt to develop non-lethal...
) - tolterodineTolterodineTolterodine is an antimuscarinic drug that is used to treat urinary incontinence.It is marketed by Pfizer in Canada and the United States by its brand name Detrol. In Egypt it is also found under the trade names Tolterodine by Sabaa and Incont L.A...
- oxybutyninOxybutyninOxybutynin is an anticholinergic medication used to relieve urinary and bladder difficulties, including frequent urination and inability to control urination , by decreasing muscle spasms of the bladder. It competitively antagonizes the M1, M2, and M3 subtypes of the muscarinic acetylcholine...
- ipratropiumIpratropiumIpratropium bromide is an anticholinergic drug used for the treatment of chronic obstructive pulmonary disease and acute asthma. It blocks the muscarinic acetylcholine receptors in the smooth muscles of the bronchi in the lungs, opening the bronchi...
- darifenacinDarifenacinDarifenacin is a medication used to treat urinary incontinence. It used to be marketed by Novartis; however in 2010 US rights for were sold to Warner Chilcott for 400 million US$....
- tiotropiumTiotropiumTiotropium bromide is a long-acting, 24 hour, anticholinergic bronchodilator used in the management of chronic obstructive pulmonary disease . Tiotropium bromide capsules for inhalation are co-promoted by Boehringer-Ingelheim and Pfizer under the trade name Spiriva...
- Zamifenacin ((3R)-1-[2-(1-,3-Benzodioxol-5-yl)ethyl]-3-(diphenylmethoxy)piperidine, CAS# 127308-98-9)
Interactions
Muscarinic acetylcholine receptor M3 has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with Arf6
Arf6
ADP-ribosylation factor 6 is a member of the ADP ribosylation factor family of GTP-binding proteins. ARF6 has a variety of cellular functions that are frequently involved in trafficking of biological membranes and transmembrane protein cargo...
and ARF1
ARF1
ADP-ribosylation factor 1 is a protein that in humans is encoded by the ARF1 gene.-Interactions:ARF1 has been shown to interact with GGA3, PLD2, COPB1 and Muscarinic acetylcholine receptor M3.-Further reading:...
.