Nicotinic receptors neuromuscular junction

While most of the muscle relaxants exert their predominant actions at the post-junctional nicotinic receptors, many also have variable pre-junctional effects. Although pre-junctional receptors have not been demonstrated there is putative evidence for their existence. The pre-junctional mechanisms are supposed to be responsible for the development of fade in response to tetanic or train-of-four (TOP) stimulation following administration of non-depolarising neuromuscular blocking drugs. 

As distinct from the acetyl choline receptor of the neuromuscular junction, the acetyl receptors of the viscera are not blocked by nicotine but are blocked by muscarine. Moreover, based on differences in the binding of the muscarinic antagonist, pirenzapine, the muscarinic acetyl choline receptors (mAChRs), are separated into two classes, viz. high affinity mj receptors, and low affinity m2 receptors. The latter predominates in the heart, cerebellum, and smooth muscle broadly. These different receptors mediate quite different actions. 

Another possible target for toxins are the receptors for neurotransmitters since such receptors are vital, especially for locomotion. In vertebrates the most strategic receptor is that for acetylcholine, the nicotinic receptor. In view of the breadth of action of the various conotoxins it is perhaps not surprising that alpha-conotoxin binds selectively to the nicotinic receptor. It is entirely possible that similar blockers exist for the receptors which are vital to locomotion in lower species. As mentioned previously, lophotoxin effects vertebrate neuromuscular junctions. It appears to act on the end plate region of skeletal muscle (79,59), to block the nicotinic receptor at a site different from the binding sites for other blockers (81). 

To achieve their different effects NTs are not only released from different neurons to act on different receptors but their biochemistry is different. While the mechanism of their release may be similar (Chapter 4) their turnover varies. Most NTs are synthesised from precursors in the axon terminals, stored in vesicles and released by arriving action potentials. Some are subsequently broken down extracellularly, e.g. acetylcholine by cholinesterase, but many, like the amino acids, are taken back into the nerve where they are incorporated into biochemical pathways that may modify their structure initially but ultimately ensure a maintained NT level. Such processes are ideally suited to the fast transmission effected by the amino acids and acetylcholine in some cases (nicotinic), and complements the anatomical features of their neurons and the recepter mechanisms they activate. Further, to ensure the maintenance of function in vital pathways, glutamate and GABA are stored in very high concentrations (10 pmol/mg) just as ACh is at the neuromuscular junction. 

Drugs that block the nicotinic receptors on autonomic ganglia, such as hexamethonium, probably do so by actually blocking the Na+ ion channel rather than the receptor. Generally these receptors appear to resemble the central ones more than those at the neuromuscular junction and dihydro-jS-erythroidine is one drug that it is an effective antagonist in both ganglia and the CNS. 

Neuromuscular Nicotinic receptors are responsible for transmission at the neuromuscular junction. While briefly causing stimulation, this phase is rapidly obscured by desensitization and neuromuscular blockade. Thus, nicotine has muscle-relaxant effects. 

Many receptors for neurotransmitters function as ligand-gated channels for Na and/or Ca " ions (see p. 354). The ones that have been studied in the greatest detail are the nicotinic receptors for acetylcholine (see p. 352). These consist of five separate but structurally closely related subunits. Each forms four transmembrane helices, the second of which is involved in the central pore in each case. The type of monomer and its arrangement in the complex is not identical in all receptors of this type. In the neuromuscular junction (see p. 334), the arrangement aPya8 is found (1). 

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