Central nervous system receptors, acetylcholinesterase

Diazinon, an anticholinesterase organophosphate, inhibits acetylcholinesterase in the central and peripheral nervous system. Inhibition of acetylcholinesterase results in accumulation of acetylcholine at muscarinic and nicotinic receptors leading to peripheral and central nervous system effects. These effects... 

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. 

Symptoms (a) are due to the excess acetylcholine at muscarinic receptors. Symptoms (b) are due to excess acetylcholine at nicotinic receptors. Symptoms (c) are due to the accumulation of acetylcholine in the central nervous system. Acetylcholine accumulates because the organophosphates inhibit the enzyme acetylcholinesterase which normally removes the neurotransmitter substance. 

A. Organophosphorus (OP) compounds inhibit the enzyme acetylcholinesterase (AChE), allowing the accumulation of excessive acetylcholine at muscarinic receptors (cholinergic effector cells), at nicotinic receptors (skeletal neuromuscular junctions and autonomic ganglia), and in the central nervous system. 

Like other nerve agents, VX works by disrupting the central nervous system. The neurotransmitter acetylcholine (ACh) passes messages across synapses (gaps between neurons). When its job is done, it is released by the receptor and has to be destroyed, otherwise the ACh build up would lead to overstimulation of the nervous system. This is done by the enzyme acetylcholinesterase (AChE). 

Metabolites that are less reactive than suicide inhibitors may impact more distant enzymes, within the same cell, adjacent cells, or even in other tissues and organs, far removed from the original site of primary metabolism. For example, organopho-sphates (OPs), an ingredient in many pesticides, are metabolized by hepatic CYPs to intermediates, which, when transported to the nervous system, inhibit esterases that are critical for neural function. Acetylcholinesterase (AChE) catalyzes the hydrolysis of the ester bond in the neurotransmitter, acetylcholine, allowing choline to be recycled by the presynaptic neurons. If AChE is not effectively hydrolyzed by AChE in this manner, it builds up in the synapse and causes hyperexcitation of the postsynaptic receptors. The metabolites of certain insecticides, such as the phos-phorothionates (e.g., parathion and malathion) inhibit AChE-mediated hydrolysis. Phosphorothionates contain a sulfur atom that is double-bonded to the central phosphorus. However, in a CYP-catalyzed desulfuration reaction, the S atom is... 

Excess toxicity of varying extents occurs for acetylcholinesterase (AChE) inhibitors such as organophosphorous compounds (Bruijn and Hermens, 1991a,b). Acetylcholine serves as a neurotransmitter in the central as well as in the peripheral nervous systems of various vertebrates and invertebrates (Corbett, Wright and Baillie, 1984 Fukuto, 1990). When an efferent impulse reaches the nerve ending, acetylcholine is released into the synaptic cleft and diffuses to receptors located in the postsynaptic membrane, causing stimulation of the nerve fibre or the muscle. The quaternary ammonium of the acetylcholine binds by electrostatic interactions to the receptors anionic centre... 

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