Neuromuscular junction

[BJA CEPD Reviews 2002 Vol 2(5) "Physiology of neuromuscular junction"]

Presynpatic neuron

Motor neuron

• Cell bodies are in ventral horn of the spinal cord
• Myelinated

Motor unit

• A muscle cell has only one neuromuscular junction, and only innervated by one nerve
• A nerve, and the group of muscle cells that it innervates comprise a motor unit

Prejunctional nicotinic ACh receptors

• Prejunctional nAChRs influence the release of acetylcholine
• Differ from postjunctional nAChRs in
  * Chemical binding characteristics
  * The nature of ion channel they control (some are Ca2+ channels, some are Na+ channels)
  * Preferential blockade during high-frequency stimulation

Acetylcholine storage

• ACh are stored in the vesicles in the axon terminal
• 1% of the vesicles are available for immediate release
• About 80% of the ACh are in reserve pool
  * Released in response to nerve impulses
• The remainder is the stationary store
• Each vesicle contains about 12,000 molecules of ACh
  * Or 5,000 - 10,000 molecules [SH4:p214]
• ACh is loaded into the vesicles by a magnesium-dependent proton pump ATPase

Postsynaptic muscle cell

Motor end plate

• A small specialised area on the muscle cell
• Very rich in ACh receptors (10,000-20,000 per square micrometer)
• 1-10 million receptor per end plate

Extrajunctional receptors

• Extrajunctional receptors differ from junctional receptors
• Extrajunctional receptors increase in number when there is deficient stimulation of the skeletal muscle
  * e.g. after denervation injury, burn, or CVA
  * Not found in normal active muscles
• Extrajunctional receptors has shorter halflife (<24 hours)
  * c.f. Normal junctional ACh receptors is about 14 days
• Extrajunctional receptors are highly sensitive to ACh and suxamethonium
  --> Open for longer
  * But ion conductance is smaller
• Extrajunctional receptors tend to be concentrated around the end plates, but can also be found anywhere on the (postjunctional) muscle membrane
• Similar pentameric structure with 5 subunits, but have the foetal delta subunit increased of the normal adult epsilon subunit

Clinical relevance

Where there is a large number of extrajunctional receptors

• Resistance to non-depolarising muscle relaxants
• Increased sensitivity to depolarising muscle relaxants
  --> Hyperkalaemic response can be exaggerated

Physiological events

Release of ACh

• Nerve impulse reach nerve terminal
  --> Type P Ca2+ channel in the terminal membrane opens
  --> Ca2+ flows into the nerve terminal
  --> Release of contents of 50-100 vesicles, and the reserve vesicles is moved to the release sites (active zones)
• ACh diffuses into the synaptic (or junctional) cleft
  --> Binds to nicotinic ACh receptors on the post-junctional membrane
  --> Conformational change in the receptors
  --> Cations (Na+, K+, Ca2+) are able to pass through the channel (ligand-gated channel)
  --> Depolarisation
• When the threshold of -50mV is reached
  --> Voltage-gated Na+ channel on the sarcolemma open
  --> Inflow of Na+ into muscle cell
  --> Action potential
• ACh not bound to a receptor, or dissociates from the receptors
  --> Quickly broken down by acetylcholinesterase

NB:

• Only 6-25% of the ACh released normally is needed to reach the threshold potential, and thus causing AP
• Release of vesicles is Ca2+ dependent
• Movement of ACh from synthesis sites to release sites is Na+ dependent