Acetylcholinesterase neuronal

Figure 10.1-12. Distribution of compounds in the layer of acetylcholinesterase inhibitors neurons colored m black and marked with a circle contain i inhibitors of acetylcholinesterase, and neurons in light gray contain other compounds.

Acetylcholine serves as a neurotransmitter. Removal of acetylcholine within the time limits of the synaptic transmission is accomplished by acetylcholinesterase (AChE). The time required for hydrolysis of acetylcholine at the neuromuscular junction is less than a millisecond (turnover time is 150 ps) such that one molecule of AChE can hydrolyze 6 105 acetylcholine molecules per minute. The Km of AChE for acetylcholine is approximately 50-100 pM. AChE is one of the most efficient enzymes known. It works at a rate close to catalytic perfection where substrate diffusion becomes rate limiting. AChE is expressed in cholinergic neurons and muscle cells where it is found attached to the outer surface of the cell membrane. 

Figure 6.2 Diagrammatic representation of a cholinergic synapse. Some 80% of neuronal acetylcholine (ACh) is found in the nerve terminal or synaptosome and the remainder in the cell body or axon. Within the synaptosome it is almost equally divided between two pools, as shown. ACh is synthesised from choline, which has been taken up into the nerve terminal, and to which it is broken down again, after release, by acetylcholinesterase. Postsynaptically the nicotinic receptor is directly linked to the opening of Na+ channels and can be blocked by compounds like dihydro-jS-erythroidine (DH/IE). Muscarinic receptors appear to inhibit K+ efflux to increase cell activity. For full details see text...

Greenfield, SA (1991) A noncholinergic action of acetylcholinesterase (AchE) in the brain. From neuronal secretion to the generation of movement. Cell. Mol. Neurohiol. 11 55-77. 

The primary mechanism used by cholinergic synapses is enzymatic degradation. Acetylcholinesterase hydrolyzes acetylcholine to its components choline and acetate it is one of the fastest acting enzymes in the body and acetylcholine removal occurs in less than 1 msec. The most important mechanism for removal of norepinephrine from the neuroeffector junction is the reuptake of this neurotransmitter into the sympathetic neuron that released it. Norepinephrine may then be metabolized intraneuronally by monoamine oxidase (MAO). The circulating catecholamines — epinephrine and norepinephrine — are inactivated by catechol-O-methyltransferase (COMT) in the liver. 

Hussein, A.S., Chacon, M.R., Smith, A.M., Tosado-Acevedo, R. and Selkirk, M.E. (1999a) Cloning, expression and properties of a non-neuronal secreted acetylcholinesterase from the parasitic nematode Nippostrongylus brasiliensis. Journal of Biological Chemistry 274, 9312-9319. 

Cholinesterases are widely distributed throughout the body in both neuronal and non-neuronal tissues. Based largely on substrate specificity, the cholinesterases are subdivided into the acetylcholinesterases (AChEs) (EC... 

Diazinon exerts its toxic effects by binding to the neuronal enzyme acetylcholinesterase (AChE) for long periods after exposure. Diazinon, in turn, is converted to diazoxon, which has a higher affinity for AChE (and thus greater toxicity) than the parent compound. There is a latent period in... 

Nerve Agent Substances that interfere with the central nervous system. Organic esters of phosphoric acid used as a chemical warfare agent because of their extreme toxicity (tabun-GA, sarin-GB, soman-GD, GF, and VX). All are potent inhibitors of the enzyme, acetylcholinesterase, which is responsible for the degradation of the neurotransmitter, acetylcholine in neuronal synapses or myoneural junctions. Nerve agents are readily absorbed by inhalation and/or through intact skin. 

Figure 14.9 Axonal transport of enzymes, neurotransmitter synthesis, storage in vesicles, release and uptake by presynaptic neurone or enzymic degradation. The neurotransmitter in the synaptic cleft may be removed by the presynaptic neurone (i.e. recycling), by the postsynaptic neurone or by glial cells (not shown). Alternatively, the neurotransmitter may be degraded, and therefore inactivated, by enzyme action. For example, acetylcholine is degraded by acetylcholinesterase in the synaptic cleft (Chapter 3). One of the products, choline, is transported back into the neurone to be reacted with acetyl-CoA to re-form acetylcholine. The vesicle, once empty, may also be recycled for re-packaging (Figure 14.8).

To date, three of the four FDA-approved medications used in the treatment of the cognitive aspects of AD are acetylcholinesterase inhibitors, which increase overall levels of acetylcholine (the fourth reduces glutamate excitotoxicity via the NMD A receptor). The identification of compounds that reduce inflammation (and thus immune-mediated neuron loss) or increase the levels of acetylcholine are, therefore, also active areas of drug discovery. 

Acetylcholine is synthesized from acetyl-CoA and choline in the cytoplasm of the presynap-tic axon [1] and is stored in synaptic vesicles, each of which contains around 1000-10 000 ACh molecules. After it is released by exocy-tosis (see p. 228), the transmitter travels by diffusion to the receptors on the postsynaptic membrane. Catalyzed by acetylcholinesterase, hydrolysis of ACh to acetate and choline immediately starts in the synaptic cleft [2], and within a few milliseconds, the ACh released has been eliminated again. The cleavage products choline and acetate are taken up again by the presynaptic neuron and reused for acetylcholine synthesis [3j. 

Pharmacology Donepezil enhances cholinergic function by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase (AChE). Donepezil s effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. Pharmacokinetics ... 

Varicosity showing processes of synthesis and storage of acetylcholine within a cholinergic neuron. Also shown are the release of acetylcholine (exocytosis) and the location of acetylcholinesterase, which inactivates acetylcholine. 

The interactions between transmitters and their receptors are readily reversible, and the number of transmitter-receptor complexes formed is a direct function of the amount of transmitter in the biophase. The length of time that intact molecules of acetylcholine remain in the biophase is short because acetylcholinesterase, an enzyme that rapidly hydrolyzes acetylcholine, is highly concentrated on the outer surfaces of both the prejunctional (neuronal) and postjunctional (effector cell) membranes. A rapid hydrolysis of acetylcholine by the enzyme results in a lowering of the concentration of free transmitter and a rapid dissociation of the transmitter from its receptors little or no acetylcholine escapes into the circulation. Any acetylcholine that does reach the circulation is immediately inactivated by plasma esterases. 

Mesulam MM, Mufson EJ, Levey AI, et al Atlas of cholinergic neurons in the forebrain and upper brainstem of the macaque based on monoclonal choline acetyltransferase immuno histochemistry and acetylcholinesterase histochemistry. Neuroscience 12 669-686, 1984... 

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