The cholinergic synapses

The transmitter substances do not bind covalently to the receptor site and will diffuse off. Binding and dissociation will follow the law of mass action so that high concentrations of transmitters in the synaptic cleft will lead to more molecules binding to the receptor and stronger signals. Before the next impulse arrives, the concentration of the transmitter substance in the synaptic cleft must be reduced, either by diffusion out, uptake in the cells involved, or enzymatic degradation. Most important is the acetylcholinesterase, which degrades acetylcholine, described in the previous chapter. 

The synapses using acetylcholine (ACh) as the transmitter substance are the target for a wide variety of pesticides and therefore need a more detailed description. Acetylcholine is used as a transmitter substance in nearly all animal phyla, but at different parts of the nervous system. It is also present in single-cell animals and even in plants. Enzymes that catalyze the hydrolysis of acetylcholine, the cholinesterases, are also present in various organisms not having a nervous system. In insects and other arthropods, ACh is the transmitter of messages from sensory neurons to the central nervous system (CNS) and within the CNS, but not from motor neurons to skeletal muscles, where the transmitter is glutamate. In annelids, the excitatory transmitter for the body wall muscles is acetylcholine, as at the neuromuscular junctions in vertebrates. 

There are two types of cholinergic synapses. They are called nicotinic and muscarinic synapses, respectively, because the postsynaptic membranes have receptors that are sensitive to either nicotine or muscarine, although they are both sensitive to acetylcholine. 

Muscarine is present in certain mushrooms in many genera, notably the Inocybe and Clitocybe genera, but small amounts are also present in the fly agaric, Amanita muscaria. The ecological function of this nerve poison in the fungus is not understood. In mammals, the typical symptoms are unrest, irritability, excitement, sweating, salivation, respiratory trouble, feeble pulse, 

The muscarinic symptoms are miosis (constriction of the pupil of the eye), vomiting, diarrhea, bradychardia (slow heartbeat frequency), and cardiovascular collapse. Muscarinic symptoms are attributable to peripheral parasympathetic stimulation. 

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Diethyl 0-(3-methyl-5-pyrazolyl) phosphate (722) and 0,0-diethyl 0-(3-methyl-5-pyrazolyl) phosphorothioate (723) were prepared in 1956 by Geigy and they act, as do all organophosphates in both insects and mammals, by irreversible inhibition of acetylcholinesterase in the cholinergic synapses. Interaction of acetylcholine with the postsyn-aptic receptor is therefore greatly potentiated. 0-Ethyl-5-n-propyl-0-(l-substituted pyrazol-4-yl)(thiono)thiolphosphoric acid esters have been patented as pesticides (82USP4315008). 

Whittaker VP, editor. The cholinergic synapse. Handbook of experimental pharmacology, vol 97. Berlin, Heidelberg Springer-Verlag 1988. 

Stimulus-evoked, calcium-dependent release of acetylcholine (ACh) from the cholinergic synapse normally occurs through the formation of a fusion complex between ACh-containing vesicles and the intracellular leaflet of the nerve terminal membrane (Amon et al., 2001). This synaptic vesicle fusion complex consists of several proteins of the SNARE family, including a 25 kDa synaptosomal associated protein (SNAP-25), vesicle-associated membrane protein (VAMP, or synaptobrevin), and the synaptic membrane protein syntaxin. Other SNARE proteins have been identified as components of membrane transport systems in yeast and mammals but have not been implicated as targets for BoNTs. Meanwhile, type A and E neurotoxins cleave SNAP-25 while types B, D, F, and G act on VAMP and type C1 toxin cleaves both syntaxin and SNAP-25. Neurotoxin-mediated cleavage of any of these substrates disrupts the processes involved in the exocytotic release of ACh and leads to flaccid paralysis of the affected skeletal muscles. 

Like other organophosphorus insecticides, the active metabolite, diazoxon, elicits toxicity by inhibiting the enzyme acetylcholinesterase in the cholinergic synapse. Acetylcholinesterase inhibition leads to accumulation of the neurotransmitter acetylcholine resulting in neurotoxicity. 

Boutons immunoreactive for choline acetyltransferase (ChAT) make synaptic contacts with striatal spiny neurons as well as other striatal cells (Izzo and Bolam 1988). The cholinergic synapses are symmetric and make contact with the cell somata (20%) dendritic shafts (45%) and with dendritic spines (34%). As with the other symmetrical synapses on dendritic spines, these share the spine with an asymmetrical synapse, usually placed more distally on the spine, similar to afferents from the cerebral cortex and thalamus. 

AChE Organophosphorus insecticides Carbamates Inhibits the hydrolysis of ACh, causing overstimulation of the cholinergic synapses Nicotinic and muscarinic effects... 

The reaction is the mechanism by which acetylcholine is made for neurotransmission in the axonal terminal bulbs of the cholinergic synapse. 

Tucek S. Choline acetyltransferase and synthesis of acetylcholine. In Wittaker VP, ed. The Cholinergic Synapse Handbook of Experimental Pharmacology. Berlin Springer-Verlag, 1988, pp. 125-165. 

All three of these molecules contain highly reactive phosphoryl groups that readily react with the active-site serine of acetylcholinesterase to form a stable derivative. Without active acetylcholinesterase, synaptic transmission at the cholinergic synapses is impossible, resulting in respiratory paralysis. 

Aricept is not an experimental medication. Aricept works by preventing the breakdown of acetylcholine (Ach) by acetylcholinesterase and thereby increases the availability of Ach at the cholinergic synapses. 

The toxicodynamics (mechanism of action) of OP are known the action is based on apparently irreversible acetylcholinesterase (AChE, EC 3.1.1.7) inhibition at the cholinergic synapses. The resulting accumulation... 

AChE and BuChE differ in their enzymatic properties and physiological function (M7, D4). However, there are other types of cholinesterases like benzoylcholinesterase and propionylcholinesterase. AChE splits neuromediator acetylcholine at the cholinergic synapses. It was also observed in erythrocytes but its function here is not yet known in detail. Like the function of BuChE activity in plasma, though, there is evidence that BuChE plays an important role in cholinergic neurotransmission and could be involved in other nervous system functions, in neurological diseases, and in nonspecific detoxification processes (D4). 

The cholinergic synapse is the key target area for aU major insecticides. Nicotine and the neonicotinoids bind to the postsynaptic nicotinic acetylcholine receptor. 

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