Neuromuscular junction acetylcholine receptors

Figure 4.14 Gated ion channel (ligand activated, acetylcholine) at neuromuscular junction, (a) receptor sites unoccupied and gate closed (b) acetylcholine receptor sites occupied and gate is open allowing influx of ion...

Salpeter, M.M. (1987) Development and neural control of the neuromuscular junction and of the junctional acetylcholine receptor. Neurol. Neurobiol. 23 55-115. 

Neurotransmitters and neuropeptides Neurotransmitters are released from the presynaptic cell into the tiny volume defined by the synaptic cleft. Individual neuron contains only very small quantities of the transmitter. The released transmitter then diffuses across the cleft and binds to receptors on the post-synaptic cell. The diffusion across the short distance that separate pre- and post-synaptic neurons is fast enough to allow rapid communication between nerves or between nerve and muscle at a neuromuscular junction. acetylcholine, adrenaline noradrenaline, dopamine, serotonin, glutamate, glycine, GABA, enkephalins, substance P, angiotensin II, somatostatin... 

At the neuromuscular junction, acetylcholine interacts with receptors on the muscle end-plate. The resultant depolarization triggers an action potential which is similar to a nervous impulse (described above). For about one millisecond, acetylcholine opens channels that allow sodium ions to flow inwards, there is a temporary loss of membrane potential, and the muscle begins to contract. The acetylcholine is then destroyed by acetylcholinesterase, which is located elsewhere in the end-plate. This process occupies only a few milliseconds and can be reproduced by administering acetylcholine close to the end-plate region. However, injection directly into the interior of the muscle cell produces neither depolarization nor contraction. 

The principal arninoglycoside toxicides are neuromuscular paralysis, ototoxicity, and nephrotoxicity. Neuromuscular paralysis is a relatively rare complication resulting from high aminoglycoside concentrations at the neuromuscular junctions following, for example, rapid bolus intravenous injection or peritoneal instillation, rather than the normal intravenous infusion. The mechanism apparentiy involves an inhibition of both the presynaptic release of acetylcholine and the acetylcholine postsynaptic receptors (51). 

In the venom of C. geographus and other fish-hunting species, the conotoxins isolated so far can be divided into three major classes (1-4) o -conotoxms which block neuronal calcium channels at the presynaptic terminus of the neuromuscular junction, a-conotoxins which inhibit the acetylcholine receptor at the postsynaptic terminus, and x-conotoxins which block Na channels on the muscle membrane. 

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. 

Each muscle fiber is innervated by a branch of an alpha motor neuron. The synapse between the somatic motor neuron and the muscle fiber is referred to as the neuromuscular junction. Action potentials in the motor neuron cause release of the neurotransmitter acetylcholine. Binding of acetylcholine to its receptors on the muscle fiber causes an increase in the permeability to Na+ and K+ ions. The ensuing depolarization generates an action potential that travels along the surface of the muscle fiber in either direction that is referred to as a propagated action potential. This action potential elicits the intracellular events that lead to muscle contraction. 

Xu et al. [5] described the effect of (z>)-penicillamine on the binding of several antiacetylcholine receptor monoclonal antibodies to the Torpedo acetylcholine receptor. Penicillamine is covalently incorporated into the acetylcholine receptor through SS exchange at the cysteine residues of the a-subunit, altering the antigenic structure of the receptor. This effect on the structure of the native receptor at the neuromuscular junction may be responsible for the establishment of the autoimmune response to the acetylcholine receptor in (i))-penicillamine-induced myasthenia gravis. Cysteine and penicillamine interact to form penicillamine-cysteine mixed disulfide complexes [6] ... 

Tyrosine phosphorylation has a role in the formation of the neuromuscular synapse. For instance, the acetylcholine receptor (AChR) is concentrated at the postsynaptic membrane of the neuromuscular junction at a density of 10,000 receptors/pm2, which is about three orders of magnitude higher than that of the extrasynaptic region... 

Drugs can cause a wide variety of other autoimmune reactions. One example is myasthenia gravis, which is characterized by muscle weakness and is mediated by antibodies against the acetylcholine receptor at the neuromuscular junction. It has been reported in association with penicillamine [66], gold salts [67], and procainamide [68]. Another form of drug-induced autoimmunity is polymyositis, which is an autoimmune disease... 

The MSAL-type alkaloids are potent neuromuscular poisons in mammals, acting at the post-synaptie neuromuseular junction. Variations in structural features of eaeh norditerpenoid alkaloid ean exaeerbate or reduee toxieity. While the mechanism of action of the norditerpenoid alkaloids involves blocking of neuromuscular transmission at the al nicotinic acetylcholine receptors, relative toxicity of individual alkaloids is observed to change with variations in the structural characteristics of the alkaloids (Dobelis et al., 1999). In comparison with the lyeoetonine and MDL-type alkaloids, the high toxicity... 

At the neuromuscular junction, the terminus of the axon is separated from the sarcolemma by a cleft about 4 nm wide. When an action potential arrives at the terminus, it activates a voltage-sensitive Ca " ion channel. This results in Ca + ions diffusing into the terminus increasing the intracellular Ca + ion concentration, which stimulates exo-cytosis of acetylcholine from the terminus into the cleft. The acetylcholine diffuses across the cleft and binds to receptors on the motor end-plate (Figure 13.12) on the muscle side of the cleft. The binding of acetylcholine to... 

Stimulation of the parasympathetic system releases acetylcholine at the neuromuscular junction in the sinoatrial node. The binding of acetylcholine to its receptor inhibits adenylate cyclase activity and hence decreases the cyclic AMP level. This reduces the heart rate and hence reduces cardiac output. This explains why jumping into very cold water can sometimes stop the heart for a short period of time intense stimulation of the vagus nerve (a parasympathetic nerve) markedly increases the level of... 

Curare-like muscle relaxants act by blocking acetylcholine receptor sites, thus eliminating transmission of nerve impulses at the neuromuscular junction. There are two acetylcholine-like groupings in the molecules, and the drugs, therefore, probably span and block several receptor sites. The neurotransmitter acetylcholine is also a quaternary ammonium compound. The natural material present in curare is tubocurarine, a complex alkaloid that is a mono-quaternary salt. Under physiological conditions, the tertiary amine will be almost completely protonated (see Section 4.9), and the compound will similarly possess two positively charged centres. 

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