Acetylcholine desensitization

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. 

Another complication is receptor desensitization. Desensitization of the nicotinic acetylcholine receptor is attributed to the receptor, especially in its activated form, changing spontaneously to a desensitized, inactive state. The following is a scheme incorporating all possible desensitized states of the receptor ... 

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The desensitization of most GPCRs appears to be dependent on the carboxyl tail or third intracellular loop regions. For example, the cx -adrenergic (132), the a,g-adrenergic (133), the N-formyl peptide (134), and the M2 muscarinic acetylcholine (135,136) receptors aU contain clusters of residues in the third intracellular loop that are required for desensitization. 

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Most of the experimental evidence came initially from studies of the frog motor end-plate, where it was shown that the desensitization of the nicotinic receptor caused by continuous short pulses of acetylcholine was associated with a slow-conformational change in that the ion channel remained closed despite the fact that the transmitter was bound to the receptor surface. 

Unlike the muscarinic receptors, repeated exposure of the neuronal receptors to nicotine, both in vivo and in vitro, results in an increase in the number of receptors similar changes are reported to occur after physostigmine is administered directly into the cerebral ventricles of rats. These changes in the density of the nicotinic receptors are accompanied by an increased release of acetylcholine. Following the chronic administration of physostigmine, however, a desensitization of the receptors occurs. Functionally nicotinic receptors appear to be involved in memory formation in clinical studies it has been shown that nicotine can reverse the effects of scopolamine on short-term working memory and both... 

FIGURE 12-4 Three states of the acetylcholine receptor. Brief exposure of (a) the resting (closed) ion channel to acetylcholine (ACh) produces (b) the excited (open) state. Longer exposure leads to (c) desensitization and channel closure. 

Normally, the acetylcholine concentration in the synaptic cleft is quickly lowered by the enzyme acetylcholinesterase, present in the cleft. When acetylcholine levels remain high for more than a few milliseconds, the receptor is desensitized (Fig. 12-lc). The receptor channel is converted to a third conformation (Fig. 12-4c) in which the channel is closed and the acetylcholine is very tightly bound. The slow release (in tens of milliseconds) of acetylcholine from its binding sites eventually allows the receptor to return to its resting state—closed and resensitized to acetylcholine levels. 

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