Acetylcholine, deactivation

Symptoms resulting from an inadequate supply of acetylcholine may be relieved by blocking the body s acetylcholine-deactivating mechanism. Interest in this category of agents... 

Acetylcholine, deactivation by acetylcholinesterase, 469-470 Acetylcholinesterase, inhibition of acetylcholine, 469-470,471/... 

The chemical messenger alters the conformational state of an integral membrane protein that operates as a channel for the movement of ions (e.g., Na+, K+, Ca2+, Cl") across the plasma membrane. Excitatory neurotransmitters such as glutamate, acetylcholine and ATP activate ligandgated ion channels that promote the entry of Na+ and Ca2+ ions to depolarize (activate) neurones. The inhibitory neurotransmitter -y-aminobutyrate (GABA), on the other hand, promotes the entry of Cl- ions that hyperpolarize (deactivate) neurons. 

Bethanechol is a quaternary ammonium compound that shares both the muscarinic and nicotinic actions of acetylcholine but it is much more slowly deactivated. It has been used to treat clomipramine-induced orgasmic dysfunction (1). 

Carbachol is a quaternary ammonium compound that shares both the muscarinic and nicotinic actions of acetylcholine but is much more slowly deactivated. Carbachol has been used topically in ophthalmology and systemically (subcutaneously, for example in doses of 2 mg/day) for urinary retention. Severe cholinergic effects can result. In one instance they primarily involved the gastrointestinal tract and the patient died of esophageal rupture (1). In other cases patients have experienced extreme bradycardia with hypotension, requiring treatment with intravenous atropine. As carbachol is not destroyed by cholinesterase, a cumulative effect is possible in patients who receive regular doses at short intervals in one case, hypotension only developed on the third treatment day (2). 

The physiological activity of acetylcholine relies on local release, stimulation of the receptor, then rapid hydrolysis (deacetylation) by acetylcholinesterase, which results in deactivation. The indole alkaloid physostigmine, from the West African calabar bean, and the relatively simple synthetic compound pyridostigmine, which has a more obvious relationship to choline, are reversible inhibitors of acetylcholinesterase. Controlled inhibition of the enzyme by such drugs, which results in a build-up of ACh, is useful in conditions such as myasthenia gravis, a muscle weakness, which is caused by insufficient production of ACh. 

Organophosphorus and carbamate insecticides are the two classes of anticholinesterase insecticides. All anticholinesterases inhibit nervous tissue acetylcholinesterase, the enzyme that deactivates the neurotransmitter acetylcholine (Ecobichon 1996). Poisoning causes accumulation of acetylcholine in the synaptic cleft, resulting in continuous electrical stimulation (Chambers 1992 Costa 1988). Described best by Chambers (1992), the mechanism of acute symptoms of poisoning occurs through three pathways ... 

One major question relates to whether the nonselective cation channels activated by norepinephrine and acetylcholine are the same protein. Inoue and Kuriyama (Inoue and Kuriyama 1993) studied the activation of both currents in the rabbit portal vein, one of the few vascular preparations in which excitatory muscarinic responses are observed. Based on lack of an additional current response once Icat was fully activated by one agonist, and similar current I-V relationships, current activation and deactivation kinetics, single channel conductance, and block by Cd they concluded that adrenergic and muscarinic stimulation activates a common nonselective cation channel. On the other hand, substantial differ-... 

Choline esters are simply choline bound to an acetyl derivative by an ester bond. The ester bond of acetylcholine and related drugs is hydrolyzed by enzymes known as cholinesterases (e.g., acetylcholinesterase). Choline esters are more or less sensitive to cholinesterase deactivation depending on their chemical structure. 

Many of these effects can be explained by an interference with a central signal cascade (Fig. 5.195). Adrenaline activates adenylylcyclase, which converts adenosine triphosphate (ATP) into cyclic 3 ,5 -adenosine monophosphate (cAMP). This is a secondary messenger, which is deactivated by a phosphodiesterase to adenosine monophosphate (AMP). Dephosphorylation with a 5 -nucleotidase releases the neuromodulator adenosine, which is enriched extracellularly in the waking state and is degraded during sleep. When adenosine binds in the presynaptic cleft to adenosine-Aj-receptors of the nerve cells, the release of most neurotransmitters, like glutamate, y-aminobutyric acid, norephedrine, serotonin and acetylcholine is inhibited. In addition, adenosine inhibits adenylylcyclase. 

Acetylcholine (ACh) is a natural neurotransmitter. After release from presynaptic nerve terminals and interaction with postsynaptic acetylcholine receptors, it is deactivated by acetylcholinesterase (AChE), which... 

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