# Muscarinic acetylcholine receptor M3

The muscarinic acetylcholine receptor, also known as cholinergic/acetylcholine receptor M$_3$, or the muscarinic 3, is a muscarinic acetylcholine receptor encoded by the human gene CHRM3.
The M$_3$ muscarinic receptors are located at many places in the body, e.g., smooth muscles, the bladder, the endocrine glands, the exocrine glands, lungs, pancreas and the brain. In the CNS, they induce emesis. Muscarinic M$_3$ 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 M$_1$ muscarinic receptor, M$_3$ receptors are coupled to G proteins of class G$_q$, 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 M$_3$ receptor is G$_q$-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 M$_3$ 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 M$_3$ mediates vasoconstriction in pathologies wherein the vascular endothelium is disrupted.

### Diabetes

The muscarinic M$_3$ 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 M$_3$ receptor, which causes insulin dysregulation that may precede diabetes.

### Other

The M$_3$ 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
* 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.