Question

One treatment for acquired myasthenia gravis is acetylcholinesterase inhibitors. Where do acetylcholinesterase inhibitors have their activity in the neuromuscular junction?

Answer 1

Myasthenia gravis is a rare autoimmune condition in which antibodies produced by the immune system attack the connection between nerves and muscles (the neuromuscular junction).

Nerve impulses become blocked, causing muscles to become weak and easily tired.

Symptoms: fluctuate in severity.

Acetylcholine is a chemical messenger that carries signals between nerve and muscle. An enzyme called acetylcholinesterase breaks down acetylcholine.

Synaptic transmission at the skeletal neuromuscular junction (NMJ) is indispensable for survival of living organisms by transducing complexity of cerebral commands to muscular twitches. In the vertebrate NMJ presynaptic electrical signal is transmitted by acetylcholine (ACh) which is released from motor nerve ending, and then diffuses through synaptic cleft to activate postsynaptic nicotinic acetylcholine receptors (nAChRs) of muscle type ((α1)2β1δε)1. This, in turn, leads to membrane depolarization (postsynaptic excitatory potential), triggering action potential (AP) and muscle twitch. Impairment of neuromuscular synaptic transmission results in muscle weakness and even death if synapses of respiratory muscles are affected.

Acetylcholinesterase – Structure and Catalytical Function

AChE is a serine hydrolase mainly found at neuromuscular junctions and cholinergic brain synapses. Its principal biological role is termination of impulse transmission at cholinergic synapses by rapid hydrolysis of the neurotransmitter ACh to acetate and choline. AChE has a remarkably high specific catalytic activity, specially for a serine hydrolase - each molecule of AChE degrades about 25000 molecules of ACh per second, approaching the rate of a diffusion-controlled reaction

Some drugs that are used to treat myasthenia gravis act on acetylcholinesterase to stop the breakdown of acetylcholine. These acetylcholinesterase inhibitors increase the amount of acetylcholine available and so help muscle activation and contraction.

Donepezil

Rivastigmine

Galantamine

Carbamates