Acetylcholin Receptor, muscarinic

There are three ways to increase acetylcholine activity (1) increase the supply of acetylcholine, (2) directly stimulate acetylcholine receptors (muscarinic agonists), and (3) block the enzyme that inactivates acetylcholine (cholinesterase inhibitors). Let s take a look at each of these approaches. 

Acetylcholine receptors - muscarinic agonists There are a number of natural plant alkaloid toxins, including arecoline, muscarine and pilocarpine and green mamba snake peptides venoms, including MTl, MT2, MTS and MT4. 

Acetylcholine receptors - muscarinic antagonists Notable active solanaceous plant alkaloids include atropine and hyoscine (scopolamine). See muscarinic cholinoceptor ANTAGONISTS. 

Uses Acetylcholine as its transmitter + Nicotinic Acetylcholine receptor Muscarinic Acetylcholine receptor... 

Felder, C. C. (1995). Muscarinic acetylcholine receptors . Signal transduction through multiple effectors. FASEB j. 9, 619-625. 

Jakubic, J., and El-Fakahany, E. E. (1997). Positive coopera -tivity of acetylcholine and other agonists with allosteric ligands on muscarinic acetylcholine receptors. Mot. Pharmacol. 52 172-177. 

Positive cooperativity of acetylcholine and other agonists with allosteric ligands on muscarinic acetylcholine receptors. Mol. Pharmacol. 52 172—179. 

Lazareno, S., and Birdsall, N. J. M. (1995). Detection, quantitation, and verification of allosteric interactions of agents with labeled and unlabeled ligands at G protein-coupled receptors Interactions of strychnine and acetylcholine at muscarinic receptors. Mol. Pharmacol. 48 362-378. 

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. 

Antagonists of muscarinic acetylcholine receptors had widely been used since 1860 for the treatment of Parkinson s disease, prior to the discovery of l-DOPA. They block receptors that mediate the response to striatal cholinergic interneurons. The antiparkinsonian effects of drugs like benzatropine, trihexyphenidyl and biper-iden are moderate the resting tremor may sometimes respond in a favorable manner. The adverse effects, e.g., constipation, urinary retention, and mental confusion, may be troublesome, especially in the elderly. 

Muscarinic acetylcholine receptors (mAChRs) form a class of cell surface receptors that are activated upon binding of the neurotransmitter, acetylcholine. Structurally and functionally, mAChRs are prototypical members of the superfamily of G protein-coupled receptors. Following acetylcholine binding, the activated mAChRs interact with distinct classes of heterotrimeric G proteins resulting in the activation or inhibition of distinct downstream signaling cascades. 

Wess J (1996) Molecular biology of muscarinic acetylcholine receptors. CritRev Neurobiol 10 69-99... 

Caulfield MP, Birdsall NJM (1998) International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev 50 279-290... 

Wess J (2004) Muscarinic acetylcholine receptor knockout mice novel phenotypes and clinical implications. Annu Rev Pharmacol Toxicol 44 423-450... 

Lanzafame A A, Christopoulos A, Mitchelson F (2003) Cellular signaling mechanisms for muscarinic acetylcholine receptors. Recept Chann 9 241-260... 

Atropine acts as an antagonist of acetylcholine at muscarinic receptors, but not at nicotinic receptors. By acting as an antagonist, it can prevent overstimulation of muscarinic receptors by the excessive quantities of acetylcholine remaining in the synaptic cleft when AChE is inhibited. The dose of atropine needs to be carefully controlled because it is toxic. 

Anatoxin-a is the most potent and most stereospecific nicotinic acetylcholine receptor agonist thus far identified. It is also highly selective for nicotinic receptors over muscarinic receptors. The molecular parameters which influence the binding affinity, channel activation, channel blockade, and receptor desensitization are being studied. Modifications of the carbonyl and amine moieties can reduce or nearly eliminate the receptor agonist potency of the compounds and also determine the channel blocking characteristics. 

Levey, A, Kitt, CA, Simmonds, WF, Price, DL and Brann, MR (1991) Identification and localisation of muscarinic acetylcholine receptor proteins in brain with subtype specific antibodies. J. Neurosci. 11 3218-3226. 

Basu N, Stamler CJ, Loua KM, Chan HM. 2005a. An interspecies comparison of mercury inhibition on muscarinic acetylcholine receptor binding in the cerebral cortex and cerebellum. Toxicol Appl Pharmacol 205 71-76. 

Birdsall NJ, Farries T, Gharagozloo P, Kobayashi S, Lazareno S, Sugimoto M. Subtype-selective positive cooperative interactions between brucine analogs and acetylcholine at muscarinic receptors functional studies. Mol Pharmacol 1999 55 778-786. 

Tucek S, Proska J. Allosteric modulation of muscarinic acetylcholine receptors. Trends Pharmacol Sci 1995 16 205-212. 

Tucek S, Musilkova J, Neduoma J, Proska J, Shelkovnikov SW, Vorlicek J. Positive cooperativity in the binding of alcuronium and A-methy lscopolamine to muscarinic acetylcholine receptors. Mol Pharmacol 1990 38 674-680. 

Jakubik J, Bacakova L, El-Fakahany EE, Tucek S. Subtype selectivity of the positive allosteric action of alcuronium at cloned M M5 muscarinic acetylcholine receptors. J Pharmacol Exp Ther 1995 274 1077-1083. 

Gharagozloo P, Lazareno S, Popham A, Birdsall N. Allosteric interactions of quaternary strychnine and brucine derivatives with muscarinic acetylcholine receptors. J Med Chem 1999 42 438-445. 

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