3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.4. Physiology
                  3.1.4.2. Neurophysiology
 3.1.4.2.4. Neuromuscular junction 

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