Acetylcholine and Myasthenia Gravis

How does the neuromuscular junction work?

The neuromuscular junction is the connection between a motor nerve and muscle fiber.

The activated motor nerve triggers the release of acetylcholine (ACh), which then diffuses across the neuromuscular junction to the muscle (post-synaptic) membrane, binds to any available acetylcholine receptor (AChR), which then in turn  activates the muscle fiber, ultimately leading to a motor contractions and a volitional movement.

What happens in myasthenia?

Autoimmune (acquired) myasthenia gravis (MG) is caused by antibodies circulating in the blood stream which bind to AChRs and disrupt neuromuscular transmission in a variety of ways:

Some of these antibodies simply block the receptor’s binding sites so that ACh cannot activate the muscle membrane:


Other antibodies link the receptors together:


Which then leads to internalization of the receptors (endocytosis) and simplification of the post-synaptic membrane:


The end result is that the post synaptic membrane becomes simplified and devoid of working AChr, so there are little or no available binding sites for the released ACh to bind to:


Excess ACh is removed from the synaptic cleft by the enzyme acetylcholinesterase (AChE), which breaks it down into inactive constituents.

nmj achr

So, you can think of MG like a game of musical chairs, when some of the chairs have been taken away, and there some of the acetylcholine can’t find a place to sit down before it is gobbled up by the AChE.

musical chairs

You can tip the odds more in favor of facilitating neuromusucular transmission by inhibiting AChE, allowing ACh to stick around longer, making it more likely to find an available AChR to bond to, rather like waiting longer to remove the chairs in musical chairs.

Dr Mary Walker first uses physostigmine in MG

mg mwDr Walker was first to discover the benefits of using a acetylcholinesterase inhibitor (AChEI) in MG in 1934.  While still a house physician at St Alfege’s Hospital, Greenwich, she found herself taking care of a 56-year-old woman with severe MG.  She happened to review the case with visiting neurologist, Dr Denny Brown, who explained to Dr Walker that MG resembled the effect of curare poisoning. Dr Walker, reading that the effect of curare could be reversed by injecting physostigmine, tried this drug on her patient, with remarkable improvement. She then treated a second case, a 40-year-old woman, using prostigmine, marketed by Roche. This case was presented to the Royal Society of Medicine in December 1934, and became known as ‘The Miracle of St Alfege’s’.

The Tensilon Test

We do still (rarely) use injectable AChEIs  like prostigmine (neostigmine) for managing MG.

However, we now more often use them for diagnosing MG, and in particular the short acting drug edrophonium or Tensilon has become synonymous with the diagnosis of MG, the so-called Tensilon test.


The oral AChEI pyridostigmine or Mestinon is now widely prescribed for symptomatic treatment of MG

One thought on “Acetylcholine and Myasthenia Gravis

  1. Pingback: Plasma Exchange For Myasthenia Gravis | Neurology Update

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