Acetylcholine phosphorylated

CBs, like OPs, act as inhibitors of ChE. They are treated as substrates by the enzyme and carbamylate the serine of the active site (Figure 10.8). Speaking generally, car-bamylated AChE reactivates more rapidly than phosphorylated AChE. After aging has occurred, phosphorylation of the enzyme is effectively irreversible (see Section 10.2.4). Carbamylated AChE reactivates when preparations are diluted with water, a process that is accelerated in the presence of acetylcholine, which competes as a substrate. Thus, the measurement of AChE inhibition is complicated by the fact that reactivation occurs during the course of the assay. Carbamylated AChE is not reactivated by PAM and related compounds that are used as antidotes to OP poisoning (see Box 10.1). 

Huganir, R.L., Delcour, A.H., Greengard, P., Hess, G.P. Phosphorylation of the nicotinic acetylcholine receptor regulates its rate of desensitization. Nature. 321 774, 1986. 

Hokin, L. E. and Hokin, M. R. Effects of acetylcholine on the turnover of phosphoryl units in individual phospholipids of pancreas slices and brain cortex slices. Biochim. Biophys. Acta 18 102-110,1955. 

Tyrosine phosphorylation has a role in the formation of the neuromuscular synapse. For instance, the acetylcholine receptor (AChR) is concentrated at the postsynaptic membrane of the neuromuscular junction at a density of 10,000 receptors/pm2, which is about three orders of magnitude higher than that of the extrasynaptic region... 

Hopfield, J. F., Tank, D. W., Greengard, P. et al. Functional modulation of the nicotinic acetylcholine receptor by tyrosine phosphorylation. Nature 336 677-680,1988. 

Staley JK, Krishnan-Sarin S, Cosgrove KP, Krantzler E, Frohhch E, Perry E, Dubin JA, Estok K, Brenner E, Baldwin RM, Tamagnan GD, Seibyl JP, Jatlow P, Picciotto MR, London ED, O Malley S, van Dyck CH (2006) Human tobacco smokers in early abstinence have higher levels of beta2 nicotinic acetylcholine receptors than nonsmokers. J Neurosci 26 8707-8714 Steiner RC, Heath CJ, Picciotto MR (2007) Nicotine-induced phosphorylation of ERK in mouse primary cortical neurons evidence for involvement of glutamatergic signaling and CaMKII. J Neurochem 103 666-678... 

Pals-Rylaarsdam, R., and Hosey, M. M. (1997) Two homologous phosphorylation domains differentially contribute to desensitization and internalization of the m2 muscarinic acetylcholine receptor. J. Biol. Chem. 272, 14152-14158. 

Irreversible anticholinesterases include the organophosphorus inhibitors and ambenonium, which irreversibly phosphorylate the esteratic site. Such drugs have few clinical uses but have been developed as insecticides and nerve gases. Besides blocking the muscarinic receptors with atropine sulphate in an attempt to reduce the toxic effects that result from an accumulation of acetylcholine, the only specific treatment for organopho-sphate poisoning would appear to be the administration of 2-pyridine aldoxime methiodide, which increases the rate of dissociation of the organophosphate from the esteratic site on the enzyme surface. 

In connection with research on oximes as reactivators of phosphorylated acetylcholine esterase, a number of studies have shown that introduction of cationic micelles such... 

The ester of the phosphorous acid or organophos-phorsus inhibitors of the acetylcholine esterase phos-phorylate serine in the active center of the enzyme. The phosphorylated enzyme is extremely stable, resulting in an irreversible inhibition. The duration of action of this compounds is determined by the rate of enzyme synthesis de novo. 

The first suggestion of a practical form of antidotal therapy came in 1949 from Hestrin, who found that acetylcholinesterase (AChE) catalyzed the formation of acetohydroxamlc acid when incubated with sodium acetate and hydroxylamine. Critical in vitro studies in the next decade led to the development of a practical approach to therapy. The crucial concept in these studies was the recognition that the compound formed when AChE reacted with a phosphorus ester was a covalent phosphoryl-enzyme Intermediate similar to that formed in the hydrolysis of acetylcholine. 3 Wilson and colleagues, beginning in 1951, demonstrated that AChE inhibited by alkyl phosphate esters (tetraethyl pyrophosphate, TEPP) could be reactivated by water, but that free enzyme formed much more rapidly in the presence of hydroxylamine. 0 21 Similar results... 

Diacylglycerol, on the other hand, is lipid soluble and remains in the lipid bilayer of the membrane. There it can activate protein kinase C (PKC), a very important and widely distributed enzyme which serves many systems through phosphorylation, including neurotransmitters (acetylcholine, a,- and P-adrenoceptors, serotonin), peptide hormones (insulin, epidermal growth hormone, somatomedin), and various cellular functions (glycogen metabolism, muscle activity, structural proteins, etc.), and also interacts with guanylate cyclase. In addition to diacylglycerol, another normal membrane lipid, phos-phatidylserine, is needed for activation of PKC. The DG-IP3 limbs of the pathway usually proceed simultaneously. 

Diazinon toxicity results predominantly from the inhibition of acetylcholinesterase in the central and peripheral nervous system. The enzyme is responsible for terminating the action of the neurotransmitter, acetylcholine, in the synapse of the pre- and post-synaptic nerve endings or in the neuromuscular junction. However, the action of acetylcholine does not persist long as it is hydrolyzed by the enzyme, acetylcholinesterase, and rapidly removed. As an anticholinesterase organophosphate, diazinon inhibits acetylcholinesterase by reacting with the active site to form a stable phosphorylated complex which is incapable of destroying acetylcholine at the synaptic gutter between the pre- and post-synaptic nerve... 

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