Themuscarinic acetylcholine receptor, also known ascholinergic/acetylcholine receptor M3, or themuscarinic 3, is amuscarinic acetylcholine receptor encoded by the human geneCHRM3.[5]
The M3 muscarinic receptors are located at many places in the body, e.g., smooth muscles, thebladder, theendocrine glands, theexocrine glands, lungs, pancreas and the brain. In theCNS, they induceemesis. 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.[6] These receptors are highly expressed on pancreatic beta cells and are critical regulators of glucose homoestasis by modulating insulin secretion.[7] In general, they cause smooth muscle contraction and increased glandular secretions.[5]
Because the M3 receptor isGq-coupled and mediates an increase in intracellularcalcium, it typically causes constriction of smooth muscle, such as that observed duringbronchoconstriction. However, with respect to vasculature, activation of M3 on vascular endothelial cells causes increased synthesis ofnitric oxide, which diffuses to adjacent vascular smooth muscle cells and causes their relaxation andvasodilation, thereby explaining the paradoxical effect of parasympathomimetics on vascular tone and bronchiolar tone. Indeed, direct stimulation of vascular smooth muscle M3 mediatesvasoconstriction in pathologies wherein the vascular endothelium is disrupted.[9]
The muscarinic M3 receptor regulates insulin secretion from the pancreas[7] 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.[6]
The M3 receptors are also located in many glands, bothendocrine andexocrine glands, and help to stimulate secretion in salivary glands and other glands of the body.
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.[8] It has also been shown tointeract withArf6[13] andARF1.[13]
^abWeston-Green K, Huang XF, Lian J, Deng C (May 2012). "Effects of olanzapine on muscarinic M3 receptor binding density in the brain relates to weight gain, plasma insulin and metabolic hormone levels".European Neuropsychopharmacology.22 (5):364–373.doi:10.1016/j.euroneuro.2011.09.003.PMID21982116.S2CID31739607.
^abGautam D, Han SJ, Hamdan FF, Jeon J, Li B, Li JH, et al. (June 2006). "A critical role for beta cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo".Cell Metabolism.3 (6):449–461.doi:10.1016/j.cmet.2006.04.009.hdl:10533/177761.PMID16753580.
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Szekeres PG, Koenig JA, Edwardson JM (April 1998). "The relationship between agonist intrinsic activity and the rate of endocytosis of muscarinic receptors in a human neuroblastoma cell line".Molecular Pharmacology.53 (4):759–765.doi:10.1124/mol.53.4.759.PMID9547368.
Goodchild RE, Court JA, Hobson I, Piggott MA, Perry RH, Ince P, et al. (February 1999). "Distribution of histamine H3-receptor binding in the normal human basal ganglia: comparison with Huntington's and Parkinson's disease cases".The European Journal of Neuroscience.11 (2):449–456.doi:10.1046/j.1460-9568.1999.00453.x.PMID10051746.S2CID30498817.
Sato KZ, Fujii T, Watanabe Y, Yamada S, Ando T, Kazuko F, Kawashima K (April 1999). "Diversity of mRNA expression for muscarinic acetylcholine receptor subtypes and neuronal nicotinic acetylcholine receptor subunits in human mononuclear leukocytes and leukemic cell lines".Neuroscience Letters.266 (1):17–20.doi:10.1016/S0304-3940(99)00259-1.PMID10336173.S2CID43548155.
