Acetylcholinesterase regulation

Taylor P, Li Y, Camp S, et al. 1993. Structure and regulation of expression of the acetylcholinesterase gene. Chem Biol Interactions 87 199-207. 

Both nicotinic receptors and acetylcholinesterase are regulated tightly during differentiation and synapse formation 202... 

The answer is D. Organophosphates react with the active site serine residue of hydrolases such as acetylcholinesterase and form a stable phosphoester modification of that serine that inactivates the enzyme toward substrate. Inhibition of acetylcholinesterase causes overstimulation of the end organs regulated by those nerves. The symptoms manifested by this patient reflect such neurologic effects resulting from the inhalation or skin absorption of the pesticide diazinon. 

Jones, A.K., Bentley, G.N., Parra, W.G.O. and Agnew, A. (2002) Molecular characterization of an acetylcholinesterase implicated in the regulation of glucose scavenging by the parasite Schistosoma. The FASEB Journal 1 6, 51-69. 

The acetylcholine, in turn, is hydrolyzed by both acetylcholinesterase and plasma butyryl-cholinesterase. Choline is actively transported into nerve terminals (synaptosomes) by a high-affinity uptake mechanism. Furthermore, the availability of choline regulates the synthesis of acetylcholine (Figure 14.4). 

The pesticide family most widely used in agricultural and residential applications is the organophosphates, which affect the nervous system by reducing the ability of the enzyme acetylcholinesterase to properly regulate the concentration of the neurotransmitter acetylcholine. If acetylcholine accumulates, the nerve impulses or neurons remain active longer than usual, overstimulating the nerves and muscles and causing symptoms such as weakness or muscle paralysis and death [112]. 

The authors speculated that the antimuscarinic drugs impaired the cholinergic receptor down-regulation that would normally occur in the presence of the increased concentrations of acetylcholine caused by acetylcholinesterase inhibition. Withdrawal of the antagonist therefore abruptly exposed the receptors to high concentrations of the neurotransmitter, leading to seizures. 

Henderson, J., M. O Malley, J. Sanborn, M. Verder-Carlos and B. Wilson (1998). Comparison of Acetylcholinesterase Assays Run Under Conditions Specified by the Standard Ellman Method and Conditions Specified by a Commercial Cholinesterase Reagent Kit, Department of Pesticide Regulation, Worker Health and Safety Branch Report HS-1752, Sacramento, CA, USA. 

Khan, W.A., Dechkovskaia, A.M., Herrick, E.A., Jones, K.H., Abou-Donia, M.B. (2000). Acute sarin exposure causes differential regulation of choline acetyltransferase, acetylcholinesterase, and acetylcholine receptors in the central nervous system of the rat. Toxicol. Sci. 57 112-20. 

Nizri, E., Hanua-Amitay, Y., Sicsic, C., Lavon, L, Brenner, T. (2006). Anti-inflammatory properties of cholinergic up-regulation a new role for acetylcholinesterase inhibitors. Neuropharmacology 50 540-7. 

Rossi, S.G., Dickerson, I.M., Rotundo, R.L. (2003). Localization of the calcitonin gene-related peptide receptor complex at the vertebrate neuromuscular junction and its role in regulating acetylcholinesterase expression. J. Biol. Chem. 278 24994— 25000. 

Silman, I., di Giamberardino, L., Lyles, L., Couraud, J.Y., Barnard, E.A. (1979). Parallel regulation of acetylcholinesterase and pseudocholinesterase in normal, denervated and dystrophic chicken skeletal muscle. Nature 280 160-2. 

Acetylcholinesterase inhibitors can probably be safely used in pregnancy when needed, provided the dosage is carefully regulated. Reversible muscle weakness in a newborn infant was attributed to relative overdosage of the mother with pyridostigmine bromide (11). 

For human health, carbamates are usually regulated based on their potency for inhibiting acetylcholinesterase activity in the nervous system. Within the next two years (2004-2006), carbamate pesticides in the United States will be regulated as a mixture of compounds (rather as single compounds) with a common mechanism of action under the direction of the Food Quality Protection Act. 

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