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e-learning VIII - Myasthenia gravis and Muscle
The Neuromuscular Junction of Skeletal Muscle
The neuromuscular junction, or end plate, is the synapse between motor neurones and skeletal muscle. Although it's a relatively specialized synapse, it is very well characterized and so has served as a model of how synapses work for many years.
As you've learned in lectures, each motor neurone can make synapses with several muscle fibres and together these are termed the motor unit. What we are going to look at now is the structure of those synapses in more detail.
When a major branch of a motor neurone axon meets a muscle fibre, it splits into a series of finely branched presynaptic nerve terminals or boutons (you may see this referred to as 'arborization'). The patch of the muscle fibre membrane where these terminals make contact, is the end plate region.
At under each of the presynaptic terminals the muscle fibre membrane has a series of folds (junctional folds). It's in these junctional folds that the nicotinic acetylcholine receptors are located.
Myasthenia Gravis: Introduction
Myasthenia gravis (MG) is a disorder in which there is an autoimmune attack on skeletal muscle.
The damage that this attack causes leads to muscle weakness and fatigue. As the muscles involved in respiration are skeletal muscles, MG can ultimately be fatal but effective treatments are available and most patients will have a normal life-span. Myasthenia gravis is one of the more common autoimmune diseases, with a prevalence of 2 per 10000. Like all autoimmune diseases,
it is most common in women (about 2x more frequent than in men) and occurs most commonly between the ages of 20 and 40.
The causes of MG are currently unknown. However, it may be that the thymus gland plays a key role. Removal of the thymus gland can prove beneficial for many patients, and a substantial number of MG suffers turn out to have problems with the thymus gland such as tumours
The target of the autoimmune attack is the nicotinic receptor on the muscle membrane. This ligand-gated ion channel is the "molecular switch" that triggers muscle contraction. Clearly, if the function of this receptor is compromised, then so too will be contraction. The Nicotinic Acetylcholine Receptor
How the nicotinic acetylcholine receptor (nAChR) participates in the generation of muscle action potentials has been covered in lectures. However, to understand myasthenia gravis fully, we need to know a little bit more about the receptor's structure.
The nAChR is a pentameric transmembrane protein. There are two alpha subunits (α), a beta ), a beta
(2), a delta (3) and an epsilon (ε). In the foetal receptor, there is a gamma subunit (γ) ). In the foetal receptor, there is a gamma subunit (γ) )
instead of ε). In the foetal receptor, there is a gamma subunit (γ) .
All of the subunits are very similar in structure; they have four transmembrane domains and a large extracellular N terminus. Amino acids in the α), a beta subunits (primarily) and in 3 and ε). In the foetal receptor, there is a gamma subunit (γ) come together to form two binding sites for acetylcholine in the extracellular part of the receptor.
The second transmembrane domains of each subunit come together to form the lining of the ion channel.
If you examine the antibodies produced in MG, it quickly becomes obvious that most of them target the same part of the nAChR. This region, known as the main immunogenic region
(MIR), is in the extracellular part of the α), a beta subunits, specifically amino acids 67-76.
When the immune system attacks the nAChR, the function of the muscle is compromised.
1) The internalisation of the receptors.
2) The destruction and simplification of the end plate.
3) The blockage of the acetylcholine binding sites.
Diagnosis of Myasthenia Gravis
There are several different diagnostic tests that can be used to tell if someone has MG. Not all patients show exactly the same pattern of symptoms and so often more than one test is needed to confirm diagnosis.
Pattern of Muscle Weakness
The muscle weakness in Myasthenia Gravis is not usually accompanied by pain but sufferers
may feel overwhelmingly fatigued. The first muscles to be affected are usually in the face:
drooping eyelids and difficulty smiling are typical early symptoms. The patient may also experience difficulty swallowing and have slurred speech. Later, muscles in the limbs and trunk may be affected.
Presence of Antibodies Against the nAChR
Testing the patient's serum will often reveal the presence of antibodies against the nicotinic receptor. Not all patients have high levels of antibodies, however, especially those people whose symptoms are predominantly limited to their eyes.
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