The muscarinic acetylcholine receptor, also known as cholinergic/acetylcholine receptor M₃, or the muscarinic 3, is a

muscarinic acetylcholine receptor Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end- ...

encoded by the human gene CHRM3. The M₃ muscarinic receptors are located at many places in the body, e.g., smooth muscles, the

endocrine The endocrine system is a messenger system comprising feedback loops of the hormones released by internal glands of an organism directly into the circulatory system, regulating distant target organs. In vertebrates, the hypothalamus is the neur ...

glands, the

exocrine glands Exocrine glands are glands that secrete substances on to 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 and throwing up) is the involuntary, 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, gastroenteriti ...

. 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 G_q, 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 ...

and, therefore, inositol trisphosphate and intracellular

calcium Calcium is a chemical element with the 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 ...

as a signalling pathway. The calcium function in vertebrates 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 ...

and its effects.

Effects

Smooth muscle

Because the M₃ receptor is G_q-coupled and mediates an increase in intracellular

, 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 Nitric oxide (nitrogen oxide 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 denoted by a dot in its ...

, which diffuses to adjacent vascular smooth muscle cells and causes their relaxation and

vasodilation Vasodilation 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. The process is the opposite of vasoconstrictio ...

, 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 vess ...

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

and

exocrine gland Exocrine glands are glands that secrete substances on to 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 ...

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 gastrointestinal tract of humans and many other animals, including several invertebrates. The stomach has a dilated structure and functions as a vital organ in the digestive system. The stomach i ...

* eye accommodation

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 chemical 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 *

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 var ...

* L-689,660 (mixed M1/M3 agonist) * oxotremorine *

pilocarpine Pilocarpine is a medication used to reduce pressure inside the eye and treat dry mouth. As eye drops it is used to manage angle closure glaucoma until surgery can be performed, ocular hypertension, primary open angle glaucoma, and to bring a ...

(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 given ...

tramadol Tramadol, sold under the brand name Ultram among others, is an opioid pain medication used to treat moderate to moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an ...

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 henbane, mandrake, angel's trumpets, jims ...

* aclidinium bromide * 4-DAMP (1,1-Dimethyl-4-diphenylacetoxypiperidinium iodide, CAS# 1952-15-4) * darifenacin *

diphenhydramine Diphenhydramine (DPH) is an antihistamine and sedative mainly used to treat allergies, insomnia, and symptoms of the common cold. It is also less commonly used for tremor in parkinsonism, and nausea. It is taken by mouth, injected into ...

fluoxetine Fluoxetine, sold under the brand names Prozac and Sarafem, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used for the treatment of major depressive disorder, obsessive–compulsive diso ...

* 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) * ipratropium * J-104,129 ((aR)-a-Cyclopentyl-a-hydroxy-N- -(4-methyl-3-pentenyl)-4-piperidinylenzeneacetamide, CAS# 244277-89-2) * oxybutynin * procyclidine * tiotropium * tolterodine * zamifenacin ((3R)-1-

-(1-,3-Benzodioxol-5-yl)ethyl The hyphen-minus is the most commonly used type of hyphen, widely used in digital documents. It is the only character that looks like a minus sign or a dash in many character sets such as ASCII or on most keyboards, so it is also used as such. ...

3-(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, doing business as, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex trai ...

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 protei ...

and ARF1.

References

External links

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