Parasympathetic synapses

Even though the muscarinic receptor, which is present in postganglionic parasympathetic synapses, is much more stereospecific and structure-specific than its nicotinic counterpart, only since the 1980s have any molecular studies been undertaken to explore similarities and differences between the two classes of AChR. It has been labeled with the affinity label pH] propyl-benzilylcholine-mustard (4.5). 

Once translocated into the cytosol, the toxic fragments exert their paralytic effects by inhibiting ACh release from neuromuscular junctions as well as other peripheral cholinergic sites, including sympathetic and parasympathetic ganglia and post-ganglionic parasympathetic synapses (Lamanna, 1959 Vincenzi, 1967 Simpson, 2004). 

The clinically useful anticholinesterase agents diisopropyl fluorophosphate (DFP, Floropryl) and echothiophate iodide (Phospholine Iodide [PI]) demonstrate an indirect-acting mechanism resulting in increased levels of acetylcholine at the cholinergic receptor sites. The inhibition of acetylcholinesterase produces a relatively long-lasting and irreversible effect of maintaining active levels of acetylcholine at the parasympathetic synapses. 

The other branch of the autonomic nervous system is the parasympathetic branch, which in general balances the actions of the sympathetic branch by exerting opposite effects. Parasympathetic activity reduces heart rate, bkxxl pressure, and so on. In contrast to sympathetic neurons, parasympathetic synapses arc primarily cholinergic. 

Acetylcholine is an essential neurotransmitter that affects parasympathetic synapses (autonomic and CNS), sympathetic preganglionic synapses, and the neuromuscular junction (see also prior section on Toxic Syndromes). Hydrolysis of acetylcholine by acetylcholinesterase, which is present in nerve tissue, normally Limits the duration of action of this neurotransmitter and allows for normal synaptic function. Organophosphate (e.g., Malathion, Parathion, Diazinon,... 

Blocking of parasympathetic synapses can be demonstrated by the inhibition of the effects of vagal stimulation. The doses required to block parasympathetic transmission are higher than those necessary for sympathetic block. With C-... 

Although the specificity of receptors is not so strict as that of the most important anabolic and catabolic enzymes, it is at least as strict as the degrad-ative enzymes of microsomes (see Section 3.5). Thus at ganglia, nicotine (but not muscarine) can take the place of acetylcholine, whereas at postganglionic parasympathetic synapses, muscarine (but not nicotine) can take its place (see Table 7.1). Further specificity is shown in acetylcholine antagonism, for which tubocurarine is specific at the neuromuscular junction, hexamethonium at ganglia, and atropine at parasympathetic postganglionic synapses. 

BoTx acts at the nerve terminal of cholinergic synapses and blocks the release of ACh (see Chap. 6), after being taken up into the vesicles and translocated to the cytoplasm where the toxin catalyses proteolysis of components involved in the calcium-mediated exocytosis of ACh. The inhibition is permanent, and recovery occurs only after the creation of new terminal boutons. The toxin thus blocks neurotransmission, parasympathetic synapses and peripheral ganglia. Conventionally... 

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