The Biochemistry of Myasthenia Gravis
- medyouthalliance
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Written by Titilayo Taoreed
Med Youth Alliance | March 2026
What is Myasthenia Gravis?
•Etymology: a phrase in Latin which translates to ‘grave muscle weakness’
•It is a chronic autoimmune disorder of the post-synaptic membrane at the neuromuscular junction in skeletal tissue
Characterised by muscle weakness that increases with exercise and improves with rest
The History of Myasthenia Gravis and Acetylcholine
• ACh was first discovered to be biologically active in 1906 when it was found that it decreased blood pressure in tiny doses.
•Earlier, it was noted in 1899 that choline injections decreased the blood pressure in animals
•The concept of neurotransmitters was unknown until 1921 when Otto Loewi observed that the vagus nerve secreted a substance that inhibited the heart muscle.
•This led to the confirmation that Acetylcholine was a neurotransmitter in 1936
The Physiology of Myasthenia Gravis
•Ordinarily, Acetylcholine is released from the axon* and transported through the presynaptic membrane to bind the acetyl choline receptors on the post synaptic membrane.
•These receptors are called Nicotinic receptors and muscarinic receptors
•After binding to these receptors, there is an influx of Ca 2+ ions which binds to troponin causing a conformational change in the troponin-tropomyosin complex, which exposes myosin-binding sites on actin filaments
•Myosin heads then bind to actin, pull the filaments past each other and generate muscle contraction
•However, in the case of Myasthenia Gravis those receptors are blocked by acetylcholine receptor antibodies. Preventing acetylcholine from binding to it and stimulating muscle contraction
•As a result, during increased muscle activity, more receptors are blocked leading to less effective stimulation of the muscle and increased muscle weakness. This contributes towards the symptoms patients present.
So how do the AChR antibodies work?
•The antibodies have a Y shape : The arms (Fab regions) the part that binds to the target
•The stem (Fc region) recruits the immune system for destruction
•How do the antibodies bind?
•They first recognise the epitopes of the AChR antibodies. Most bind to the alpha subunit that is critical for binding to acetylcholine.
•Then the Fab region locks onto these epitopes using hydrogen bonds and electrostatic interactions
•Through this the antibody physically blocks Ach from attaching, it also triggers receptor internalisation, causing the cell to pull the receptor inside and destroy it
•It also activates complement proteins which form a membrane attack complex that damages the muscle membrane
Symptoms
Muscle weakness mainly affects the
•Proximal muscles
•Small muscles of the face and neck
Causing:
•Extraocular muscle weakness -> double vision
•Eyelid muscle weakness -> drooping
•Facial weakness
Let's focus on Acetylcholine…
•It is a choline molecule that has been acetylated at the oxygen atom
•It is an excitory neurotransmitter
•However, because it has a charged ammonia group it can't pass through the lipid membrane via simple diffusion.
•So how is it transported across the presynaptic membrane?
•Vesicular Exocytosis
•ACh is stored in synaptic vesicles and when action potential arrives Ca2+ ions enters the presynaptic neuron, causing the synaptic vesicle to fuse with the presynaptic membrane. Releasing the Ach to the synaptic cleft by exocytosis.
Biochemistry of Acetylcholine
•Acetylcholine is synthesised in cholinergic neurons by the enzyme choline acetyltransferase from the compounds choline and Acetyl-CoA (acetyl coenzyme A, which comes form glucose)
•Choline is naturally present in foods, including egg yolks, soy, liver, seeds of vegetables.
•Choline is also made in your liver
•The main function of acetyl- CoA is to deliver an acetyl group to the citric cycle to be oxidised for energy production
References:
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