Muscarinic acetylcholine receptor sites

Certain plants of the family Solanaceae, such as Atropa belladonna L., Hyoscyamus niger L., and Datura stramonium L., have been used medicinally for centuries in Europe because they contain tropane-type alkaloids.For example, atropine (1) [a racemic mixture of (+)- and (—)-hyoscyamine (2)] and (-)-hyoscyamine are competitive antagonists at the muscarinic acetylcholine receptor site, leading to antispasmodic and antiallergic effects. Scopolamine [(—)-hyoscine)] (3) is used in a transdermal patch for the prevention of motion sickness. Since these tropane alkaloids penetrate the blood-brain barrier, they also have psychoactive effects. ... 

Although atropine is a known antidote against several toxic substances, its overdose can cause severe poisoning. As with other tropane alkaloids, atropine competitively blocks muscarinic acetylcholine receptor sites. This results in dilation of the pupil of the eye (mydriatic effect), dryness of the mucous membranes, especially of the mouth, and inhibition of activity of sweat glands (parasympatholytic action). At toxic doses, it causes palpitation, speech disturbance. 

Michalek, H., Fortuna, S., Volpe, M.T., et al., 1990. Age-related differences in the recovery rate of brain cholinesterases, choline acetyltransferase and muscarinic acetylcholine receptor sites after a subacute intoxication of rats with the anticholinesterase agent, isofluorophate. Acta Neurobiol. Exp. (Wars)... 

Jakubic, J., Bacakova, L., Lisd, V., El-Fakahany, E. E., and Tucek, S. (1996). Activation of muscarinic acetylcholine receptors via their allosteric binding sites. Proc. Natl. Acad. Sci. USA 93 8705-8709. 

Matsuyama, T., Luiten, P.G.M., Spencer, J. and Strosberg, A.D. (1988) Ultra-structural localisation of immunoreactive sites for muscarinic acetylcholine receptor proteins in the rat cerebral cortex. Neuroscience Research Communications 2, 69-76. 

Savarese, T. M., Wang, C. D., and Fraser, C. M. (1992) Site-directed mutagenesis of the rat ml muscarinic acetylcholine receptor. Role of conserved cysteines in receptor function. J. Biol. Chem. Thl, 11439-11448. 

Fraser CM. Wang CD, Robinson DA, Gocayne JD, Venter JC (1989) Site-directed mutagenesis of ml muscarinic acetylcholine receptors conserved aspartic adds play important roles in receptor function. Mol Pharmacol 36 840-847 Gellman RL, Kallianos JA, McNamara JO (1987) receptors mediate endogenous noradrenergic suppression of kindling development. J Pharmacol Exp Ther 241 891-898... 

Many different receptor types are coupled to G proteins, including receptors for norepinephrine and epinephrine (a- and p-adrenoceptors), 5-hydroxytrypta-mine (serotonin or 5-HT receptors), and muscarinic acetylcholine receptors. Figure 2.1 presents the structure of one of these, the uz-adrenoceptor from the human kidney. All members of this family of G protein-coupled receptors are characterized by having seven membrane-enclosed domains plus extracellular and intracellular loops. The specific binding sites for agonists occur at the extracellular surface, while the interaction with G proteins occurs with the intracellular portions of the receptor. The general term for any chain of events initiated by receptor activation is signal transduction. 

Hayashi MK, Haga T. Palmitoylation of muscarinic acetylcholine receptor m2 subtypes reduction in their ability to activate G proteins by mutation of a putative palmitoylation site, cysteine 457, in the carboxyl-terminal tail. Arch Biochem Biophys 1997 340(2) 376-382. 

Actions of acetylcholine (ACh) are referred to as muscarinic based on the observation that muscarine acts selectively at certain sites and, quahtatively, produces the same effects as ACh. Peripheral muscarinic acetylcholine receptors are found primarily on autonomic effector cells innervated by postganghonic parasympathetic nerves and on some cells that receive little or no cholinergic innervation but express muscarinic receptors e.g., vascular endothelial cells). There are also muscarinic receptors in ganglia and the adrenal meduUa, where muscarinic stimulation seems to modulate the effects of nicotinic stimulation. Within the central nervous system (CNS), the hippocampus, cortex, and thalamus have high densities of muscarinic receptors. 

Muscarinic acetylcholine receptors (mAChRs) belong to the G protein-coupled receptor (GPCR) family. To date, five distinct subtypes of mAChRs (M1-M5) have been cloned and seqnenced. They share common orthosteric ligand-binding sites... 

Gregory, K. J., Hall, N. E., Tobin, A. B., Sexton, P. M., Christopoulos, A. (2010). Identification of orthosteric and allosteric site mutations in M2 muscarinic acetylcholine receptors that contribute to ligand-selective signaling bias. The Journal of Biological Chemistry, 285, 7459-7474. 

Major site of action muscarinic-type acetylchohne receptors in the chemoreceptor trigger zone. In terms of nausea and vomiting prophylaxis, scopolamine is a competitive inhibitor of muscarinic acetylcholine receptors in the chemoreceptor trigger zone which communicates with the emetic center within the reticular formation of the brainstem. Outside the... 

Mechanism of Action Anticholinergic alkaloids that inhibit the action of acetylcholine at postganglionic (muscarinic) receptor sites. Morphine (10% of opium) depresses cerebral cortex, hypothalamus, and medullary centers. Therapeutic Effect Decreases digestive secretions, increases GI muscle tone, reduces G1 force, alters pain perception and emotional response to pain. 

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