Desensitization acetylcholine receptors

As shown in Figure 7.23, pyrethroids also bind to the acetylcholine receptor of Torpedo electric organ and vertebrate skeletal muscle. However, they do not bind to the ACh binding sites. Studies on the effects of fluvalinate on binding suggest that the action of pyrethroids is to interfere with acetylcholine receptor desensitization. It is believed that pyrethroids bind to a site that is at the lipid-protein interface and acetylcholine receptor is only a secondary target for pyrethroids (Eldefrawi and Eldefrawi, 1990). 

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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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. 

More than 90% of patients with myasthenia gravis have circulating antibodies directed against a subunit of the acetylcholine receptor/ Immunosuppressive drugs and steroids help to cut down on these autoantibodies, and many patients are benefit-ted by removal of the thymus. Newer approaches involve specific immunotherapy aimed at increasing tolerance to either T cells or to B cells.C/d For example, oral ingestion of purified acetylcholine receptors to desensitize the body s response or inhibition of production of 11-2. 

Answer A hormone can be degraded by extracellular enzymes (such as acetylcholinesterase). The GTP bound to a G protein can be hydrolyzed to GDP. A second messenger can be degraded (cAMP, cGMP), further metabolized (IP3), or resequestered (Ca2 +, in the endoplasmic reticulum). A receptor can be desensitized (acetylcholine receptor/channel), phosphorylated/inactivated, bound to an arrestin, or removed from the surface ( -adrenergic receptor, rhodopsin). 

An aspect of NAR function that is very important in its pharmacological manipulation is receptor desensitization. This phenomenon can be experimentally demonstrated in the set-up depicted in Figure 9.7 Stimulating electrodes produce presynaptic action potentials, which induce release of acetylcholine into the synaptic cleft. Acetylcholine will trigger postsynaptic action potentials, which in turn are de-... 

Figure 9.7. Desensitization of the nicotinic acetylcholine receptor. a Experimental setup. Presynaptic action potentials were triggered, and postsynaptic ones were detected using two separate sets of electrodes, b Perfusion of the synapse with extraneous acetylcholine (during the time interval indicated by the horizontal brace) brings about a sudden depolarization. Continuous presence of acetylcholine rapidly suppresses the response to presynaptic action potentials also, the membrane potential returns to levels near the resting potential. Discontinuation of the acetylcholine results in restoration of response to presynaptic stimuli.

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