Binding to muscarinic acetylcholine receptor

Nicotine affects the nervous system, interacting with the nicotinic acetylcholine receptors, and the tight binding is partially accounted for by the structural similarity between acetylcholine and nicotine. Curare-like antagonists also block nicotinic acetylcholine receptors (see Box 6.7). There are other acetylcholine receptors, termed muscarinic, that are triggered by the alkaloid muscarine. The tropane alkaloid hyoscyamine (see Box 10.9) binds to muscarinic acetylcholine receptors. 

M.B. Skaddan, M.R. Kilbourn, S.E. Snyder, P.S. Sherman, Acetylcholinesterase inhibition increases in vivo N-(2-[ F]fluoroethyl)-4-piperidyl benzilate binding to muscarinic acetylcholine receptors, J. Cereb. Blood Flow Metab. 21 (2001) 144-148. 

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. 

The modes of action of different alkaloids are diverse. For example, nicotine binds to and affects nicotinic acetylcholine receptors and shows toxicity. A recent molecular 3D model suggests that both acetylcholine and nicotine bind to the same pocket formed in a nicotinic acetylcholine receptor.15 Morphine binds to and activates opioid receptors, transmembrane-spanning G protein-coupled receptors, in the central nervous system of humans.16 Caffeine, which is structurally similar to adenine, inhibits cyclic AMP phosphodiesterase activity and inhibits the degradation of cAMP, thus exerting a toxic effect on insects 17 in human beings, binding of caffeine to the adenosine A2A receptor induces wakefulness.18 Atropine binds to muscarinic acetylcholine receptors, competing with acetylcholine, and blocks neurotransmission.1... 

Sawada, Y., Hiraga, S., Francis, B. (1990). Kinetic analysis of 3-quinuclidinyl 4-[125I]iodobenzilate transport and specific binding to muscarinic acetylcholine receptor in rat brain in vivo implications for human studies. J. Cereb. Blood Flow Metab. 10 781-807. 

Arecaidine (118), 117 and methyl substituted derivatives were tested to determine structural requirements for binding to muscarinic acetylcholine receptors [354]. Arecaidine and 117 stimulated collagen synthesis and increased proliferation of human mucosal fibroblasts [355]. Arecaidine increased micronuclei in mouse polychromatic erythrocytes, was mutagenic in V79 Chinese hamster cells [356], and induced sister-chromatid exchange in mouse bone marrow cells [357],... 

Table 4. Examples of Alkaloids Which Bind to Muscarinic Acetylcholine Receptors (mAChR) (Natural Ligand Acetylcholine)...

F fluoroethyl)-4-piperidyl benzilate binding to muscarinic acetylcholine receptors. J Cereb Blood Flow Metab 21(2) 144-148, 2001. 

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. 

Figure 9.2 Autonomic nerve pathways. All preganglionic neurons release acetylcholine (Ach), which binds to nicotinic receptors (N) on the postganglionic neurons. All postganglionic neurons in the parasympathetic system and some sympathetic postganglionic neurons innervating sweat glands release Ach that binds to muscarinic (M) receptors on the cells of the effector tissue. The remaining postganglionic neurons of the sympathetic system release norepinephrine (NE), which binds to alpha (a) or beta (P) receptors on cells of the effector tissue. The cells of the adrenal medulla, which are modified postganglionic neurons in the sympathetic system, release epinephrine (EPI) and NE into the circulation.

Through its structural similarity to acetylcholine (Figure 3.7b), muscarine binds to the acetylcholine receptor on the synapses of nerve endings of smooth muscles and endocrine glands, causing the well-known parasympaticomimetic effects. Because muscarine is not an ester like acetylcholine, and hence resists esterase activity, it is not degraded and so can cause continuous stimulation of the affected neurons. 

Fusetani N, Asai N, Matsunaga S, Honda K, Yasumuro K. (1994) Bioactive marine metabolities. 59. CyclosteUettamines A-F, pyridine alkaloids which inhibit binding of methyl quinuclidinyl benzylate (QNB) to muscarinic acetylcholine receptors, from the marine sponge, Stelletta maxima. Tetrahedron Lett 35 3967-3970. 

Tropane alkaloids are compounds known as muscarinic receptor antagonists. Atropine, its best-known member, and a number of other compounds, block the action of the neurotransmitter acetylcholine on post-ganglionic cholinergic nerves of the parasympathetic nervous system, essentially by blocking its binding to muscarinic cholinergic receptors, whereas they are much less potent at nicotinic receptor sites. 

Acetylcholine transmits all parasympathetic signals to end organs (heart, lungs, etc.) by binding to muscarinic (M) receptors. In addition, acetylcholine-plays three other important roles in neurotransmission. 

Cyclostellettamines A-F, Pyridine Alkaloids which Inhibit Binding of Methyl Quinuclidinyl Benzilate (QNB) to Muscarinic Acetylcholine Receptors, from the Marine Sponge Stelletta maxima. Fusetani, N. Asai, N. Honda, K. and Yasumuro, K. Tetrahedron Lett, 1994, 35, 3967. 

In 1936, Loewi received the Nobel Prize with Henry Dale. They discovered that acetylcholine has two types of action. The drug, atropine, produces the muscarinic effert of acetylcholine by binding to muscarinic acetyldioline receptors. Acetylcholine also has nicotinic actions, stimulating the autonomic nervous system and voluntary muscle fibers. Nicotine stimulates the noradrenergic system. It acts by opening ion chaimels across the membranes of post-synaptic neurons, which generates electrical action potentials. 

Parasympathetic stimulation decreases heart rate. Acetylcholine, the neurotransmitter released from the vagus nerve (the parasympathetic nerve to the heart), binds to muscarinic receptors and causes the following effects ... 

Therapeutic measures include 1. administration of atropine in high dosage to shield muscarinic acetylcholine receptors and 2. reactivation of acetylcholinesterase by obidoxime, which successively binds to the enzyme, captures the phosphate residue by a nucleophilic attack, and then dissociates from the active center to release the enzyme from inhibition. 

The mechanisms of action of phencyclidine and ketamine are complex (Gorelick Balster, 1995). The drugs are non-competitive antagonists at NMDA receptors, and also bind to associated phencyclidine/sigma opioid receptors. They also have agonist actions at dopamine receptors, complex interactions with both nicotinic and muscarinic acetylcholine receptors and poorly understood interactions with noradrenergic and serotonergic systems. These multiple actions may combine to produce delirium and psychotic reactions. 

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. 

An example of a receptor coupled to an ion channel is the muscarinic acetylcholine receptor, which brings about opening of a K channel on agonist binding. There is evidence that the Py subunits of the corresponding heterotrimeric G-protein are involved in opening of the ion channel. 

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