M3 Muscarinic Receptors
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The muscarinic acetylcholine receptor, also known as cholinergic/acetylcholine receptor M3, or the muscarinic 3, is a
muscarinic acetylcholine receptor Muscarinic acetylcholine receptors (mAChRs) are acetylcholine receptors that form G protein-coupled receptor, G protein-coupled receptor complexes in the cell membranes of certain neurons and other Cell (biology), cells. They play several role ...
encoded by the human gene CHRM3. The M3 muscarinic receptors are located at many places in the body, e.g., smooth muscles, the
bladder The bladder () is a hollow organ in humans and other vertebrates that stores urine from the kidneys. In placental mammals, urine enters the bladder via the ureters and exits via the urethra during urination. In humans, the bladder is a distens ...
, the
endocrine The endocrine system is a messenger system in an organism comprising feedback loops of hormones that are released by internal glands directly into the circulatory system and that target and regulate distant organs. In vertebrates, the hypotha ...
glands, the
exocrine glands Exocrine glands are glands that secrete substances onto an epithelial surface by way of a duct. Examples of exocrine glands include sweat, salivary, mammary, ceruminous, lacrimal, sebaceous, prostate and mucous. Exocrine glands are one of ...
, lungs, pancreas and the brain. In the CNS, they induce
emesis Vomiting (also known as emesis, puking and throwing up) is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose. Vomiting can be the result of ailments like food poisoning, gastroenteritis, pregna ...
. Muscarinic M3 receptors are expressed in regions of the brain that regulate insulin homeostasis, such as the hypothalamus and dorsal vagal complex of the brainstem. These receptors are highly expressed on pancreatic beta cells and are critical regulators of glucose homoestasis by modulating insulin secretion. In general, they cause smooth muscle contraction and increased glandular secretions. They are unresponsive to PTX and CTX.


Mechanism

Like the M1 muscarinic receptor, M3 receptors are coupled to G proteins of class Gq, which upregulate
phospholipase C Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role i ...
and, therefore,
inositol trisphosphate Inositol trisphosphate or inositol 1,4,5-trisphosphate abbreviated InsP3 or Ins3P or IP3 is an inositol phosphate signaling molecule. It is made by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), a phospholipid that is located in the ...
and intracellular
calcium Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...
as a signalling pathway. The
calcium function in vertebrates Calcium ions (Ca2+) contribute to the physiology and biochemistry of organisms' cells. They play an important role in signal transduction pathways, where they act as a second messenger, in neurotransmitter release from neurons, in contraction of ...
also involves activation of
protein kinase C In cell biology, protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and t ...
and its effects.


Effects


Smooth muscle

Because the M3 receptor is Gq-coupled and mediates an increase in intracellular
calcium Calcium is a chemical element; it has symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to it ...
, it typically causes constriction of smooth muscle, such as that observed during
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. Causes The condition has a number of causes, the most common bei ...
. However, with respect to vasculature, activation of M3 on vascular endothelial cells causes increased synthesis of
nitric oxide Nitric oxide (nitrogen oxide, nitrogen monooxide, or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes den ...
, which diffuses to adjacent vascular smooth muscle cells and causes their relaxation and
vasodilation Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. Blood vessel wa ...
, thereby explaining the paradoxical effect of parasympathomimetics on vascular tone and bronchiolar tone. Indeed, direct stimulation of vascular smooth muscle M3 mediates
vasoconstriction Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vesse ...
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 The endocrine system is a messenger system in an organism comprising feedback loops of hormones that are released by internal glands directly into the circulatory system and that target and regulate distant organs. In vertebrates, the hypotha ...
and
exocrine gland Exocrine glands are glands that secrete substances onto an epithelial surface by way of a duct. Examples of exocrine glands include sweat, salivary, mammary, ceruminous, lacrimal, sebaceous, prostate and mucous. Exocrine glands are one of ...
s, and help to stimulate secretion in salivary glands and other glands of the body. Other effects are: *increased secretions from
stomach The stomach is a muscular, hollow organ in the upper gastrointestinal tract of Human, humans and many other animals, including several invertebrates. The Ancient Greek name for the stomach is ''gaster'' which is used as ''gastric'' in medical t ...
* 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 Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...
*
bethanechol Bethanechol 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 l ...
*
carbachol Carbachol, also known as carbamylcholine and sold under the brand name Miostat among others, is a cholinomimetic drug that binds and activates acetylcholine receptors. Thus it is classified as a cholinergic agonist. It is primarily used for v ...
* L-689,660 (mixed M1/M3 agonist) *
oxotremorine Oxotremorine is a drug that acts as a 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 s ...
*
pilocarpine Pilocarpine, sold under the brand name Pilopine HS among others, is a lactone alkaloid originally extracted from plants of the Pilocarpus genus. It is used as a medication to reduce pressure inside the eye and treat dry mouth. As an eye drop ...
(in eye) *muscarine


Antagonists

*
atropine Atropine is a tropane alkaloid and anticholinergic medication used to treat certain types of nerve agent and pesticide poisonings as well as some types of slow heart rate, and to decrease saliva production during surgery. It is typically give ...
*
AZD9164 AZD9164 is an experimental drug that acts as a potent and selective antagonist of the Muscarinic acetylcholine receptor M3. It contains a quaternary nitrogen atom with a permanent positive charge and so is always encountered as a salt, usually pa ...
*
tramadol Tramadol, sold under the brand name Tramal among others, is an opioid analgesic, pain medication and a serotonin–norepinephrine reuptake inhibitor (SNRI) used to treat moderately severe pain. When taken by mouth in an immediate-release form ...
*
hyoscyamine Hyoscyamine (also known as daturine or duboisine) is a naturally occurring tropane alkaloid and plant toxin. It is a secondary metabolite found in certain plants of the family Solanaceae, including Hyoscyamus niger, henbane, Mandragora officina ...
*
aclidinium bromide Aclidinium bromide (INN) is a long-acting, inhaled muscarinic antagonist (LAMA) approved in the United States in July 2012 as a maintenance treatment for chronic obstructive pulmonary disease (COPD). Evidence shows that it can improve quality ...
* 4-DAMP (1,1-Dimethyl-4-diphenylacetoxypiperidinium iodide, CAS# 1952-15-4) *
darifenacin Darifenacin (trade name Enablex in United States and Canada, Emselex in the European Union) is a medication used to treat urinary incontinence due to an overactive bladder. It was discovered by scientists at the Pfizer research site in Sandwich, ...
*
diphenhydramine Diphenhydramine, sold under the brand name Benadryl among others, is an antihistamine and sedative. Although generally considered sedating, diphenhydramine can cause paradoxical central nervous system stimulation in some individuals, particula ...
*
fluoxetine Fluoxetine, sold under the brand name Prozac, among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used for the treatment of major depressive disorder, Anxiety disorder, anx ...
* DAU-5884 (8-Methyl-8-azabicyclo-3-endo .2.3ct-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 EA-3167 is a potent and long-lasting anticholinergic deliriant drug, related to the chemical warfare agent 3-quinuclidinyl benzilate (QNB) and to the bronchodilator drug tiotropium bromide. It was developed under contract to Edgewood Arsenal ...
) *
ipratropium Ipratropium bromide, sold under the trade name Atrovent among others, is a type of anticholinergic medication which is applied by different routes: inhaler, nebulizer, or nasal spray, for different reasons. The inhalant opens up the medium ...
* J-104,129 ((aR)-a-Cyclopentyl-a-hydroxy-N-
-(4-methyl-3-pentenyl)-4-piperidinyl The symbol , known in Unicode as hyphen-minus, is the form of hyphen most commonly used in digital documents. On most keyboards, it is the only character that resembles a minus sign or a dash, so it is also used for these. The name ''hyphen-min ...
enzeneacetamide, CAS# 244277-89-2) *
oxybutynin Oxybutynin, sold under the brand name Ditropan among others, is an anticholinergic medication primarily used to treat overactive bladder. It is widely considered a first-line therapy for overactive bladder due to its well-studied side effect ...
*
procyclidine Procyclidine is an anticholinergic medication, drug principally used for the treatment of drug-induced parkinsonism, akathisia and acute dystonia, Parkinson's disease, and idiopathic or secondary dystonia. Medical uses It is used in patients ...
*
tiotropium Tiotropium bromide, sold under the brand name Spiriva among others, is a long-acting bronchodilator (LAMA: long acting muscarinic antagonist) used in the management of chronic obstructive pulmonary disease (COPD) and asthma. Specifically it is ...
*
tolterodine Tolterodine, sold under the brand name Detrol among others, is a medication used to treat frequent urination, urinary incontinence, or urinary urgency. Effects are seen within an hour. It is taken by mouth. Common side effects include head ...
* zamifenacin ((3R)-1- -(1-,3-Benzodioxol-5-yl)ethyl3-(diphenylmethoxy)piperidine, CAS# 127308-98-9) *
solifenacin Solifenacin, sold as the brand name Vesicare among others, is a medicine used to treat overactive bladder and neurogenic detrusor overactivity (NDO). It may help with incontinence, urinary frequency, and urinary urgency. Benefits appear simi ...


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 Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization advocating for the legal and human rights of children with intersex traits. The organization was founded in 2006 and fo ...
with
Arf6 ADP-ribosylation factor 6 (ARF6) 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 c ...
and
ARF1 ADP-ribosylation factor 1 is a protein that in humans is encoded by the ''ARF1'' gene. Function ADP-ribosylation factor 1 (ARF1) is a member of the human ARF gene family. The family members encode small guanine nucleotide-binding proteins tha ...
.


See also

*
Muscarinic acetylcholine receptor Muscarinic acetylcholine receptors (mAChRs) are acetylcholine receptors that form G protein-coupled receptor, G protein-coupled receptor complexes in the cell membranes of certain neurons and other Cell (biology), cells. They play several role ...


References


Further reading

* * * * * * * * * * * * * * * * *


External links

* * * {{DEFAULTSORT:Muscarinic Acetylcholine Receptor M3 Muscarinic acetylcholine receptors