Muscarinic acetylcholine receptor m3
|Cholinergic receptor, muscarinic 3|
The M3 muscarinic receptors are located at many places in the body, e.g., smooth muscles, the endocrine glands, the exocrine glands,lungs, pancreas and the brain. In the CNS, they induce emesis. 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.
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.
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.
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 effects are:
No highly selective M3 agonists are yet available as of 2009, but a number of non-selective muscarinic agonists are active at M3.
- L-689,660 (mixed M1/M3 agonist)
- pilocarpine (in eye)
- 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)
- 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-3167)
- Zamifenacin ((3R)-1-[2-(1-,3-Benzodioxol-5-yl)ethyl]-3-(diphenylmethoxy)piperidine, CAS# 127308-98-9)