Ligand binding muscarinic receptors

Bliiml, K Mutschler, E., Wess, J., 1994. Functional role in ligand binding and receptor activation of an asparagine residue present in the sixth transmembrane domain of all muscarinic acetylcholine receptors. J. Biol. Chem. 269, 18870-18876. 

Because the SSRIs are derived from different chemical groups, their receptor interactions vary from compound to compound but, apart from paroxetine, none of them shows any appreciable binding to muscarinic receptors, a prime objective of their development. However, compared with other SSRIs, fluoxetine binds with moderately high affinity to human 5-HT2A (.K) 280 nM) and 5-HT2C receptors (Aij 55 nM) sertraline is a relatively potent ligand for ai-adrenoceptors, 2-adrenoceptors and Dj receptors and citalopram shows appreciable binding to 5-HTia, oc]-adrenoceptors and Hi receptors (Table 20.6 Stanford 1996). The extent to which any of these receptor interactions affects the efficacy of these compounds is not known. 

Muscarinic receptor activation causes inhibition of adenylyl cyclase, stimulation of phospholipase C and regulation of ion channels. Many types of neuron and effector cell respond to muscarinic receptor stimulation. Despite the diversity of responses that ensue, the initial event that follows ligand binding to the muscarinic receptor is, in all cases, the interaction of the receptor with a G protein. Depending on the nature of the G protein and the available effectors, the receptor-G-protein interaction can initiate any of several early biochemical events. Common responses elicited by muscarinic receptor occupation are inhibition of adenylyl cyclase, stimulation of phos-phoinositide hydrolysis and regulation of potassium or other ion channels [47] (Fig. 11-10). The particular receptor subtypes eliciting those responses are discussed below. (See also Chs 20 and 21.)... 

Mattera, R., Pitts, B. J., Entman, M. L., and Bimbaumer, L. (1985) Guanine nucleotide regulation of a mammalian myocardial muscarinic receptor system. Evidence for homo-and heterotropic cooperativity in ligand binding analyzed by computer-assisted curve fitting. J. Biol. Chem. 260,7410-7421. 

Acetylcholine (ACh) is an example of an endogenous neurotransmitter that binds to more than one receptor type, the nicotinic acetylcholine receptor (nAChR) which preferentially binds nicotine and the muscarinic receptor which binds muscarine, a mushroom alkaloid. The latter is a G protein-coupled receptor while the nACh receptor is an excitatory ligand-gated ion channel that transports Na-i- ions. Nicotinic cholinergic receptors are found in the CNS, autonomic ganglia, and at the neuromuscular junction of skeletal muscles. They are a possible target for anaesthetics. 

Muscarinic M3 Exocrine glands, vessels (smooth muscle and endothelium) CNS neurons Like M receptor-ligand binding... 

Five subtypes of muscarinic receptors have been identified, primarily on the basis of data from ligand-binding and cDNA-cloning experiments (see Chapters 6 and 7). A standard terminology (M4 through M5) for these subtypes is now in common use, and evidence — based mostly on selective agonists and antagonists—indicates that functional differences exist between several of these subtypes. 

Aronstam RS, Eldefrawi ME. 1979. Transition and heavy metal inhibition of ligand binding to muscarinic acetylcholine receptors from rat brain. Toxicol Appl Pharmacol 48 489-496. 

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