FRCA Notes

Toxins at the Neuromuscular Junction

  • Naturally occurring venoms and toxins target both post-synaptic nAChR and pre-synaptic proteins involved in ACh vesicle release
  • Snake venom characteristically contains toxins that affect the NMJ and coagulability
  • Venom toxins affecting the NMJ can be classified as:
  1. ɑ-neurotoxins acting post-synaptically
    • E.g. ɑ-bungarotoxin from the banded krait (although there are >100 ɑ-neurotoxins)
    • Bind the ɑ-subunit of the nAChR causing irreversible nAChR inhibition
    • Are more readily reversed by anti-venoms

  2. β-neurotoxins acting pre-synaptically
    • E.g. β-bungarotoxin from the banded krait
    • Inhibit pre-synaptic release of acetylcholine
    • Are difficult to reverse and 70% of NMJ's are destroyed within 24hrs
    • Management is supportive, including ventilation

Tetanospasmin

  • The bacteria Clostridium tetani produces two toxins:
    • Tetanospasmin
    • Exotoxin tetanolysin

  • Contained in spores from bacteria found in the soil
  • Lethal dose of 1ng/kg

  • Tetanospasmin is taken up pre-synaptically and transported retrogradely
  • It inhibits GABA and glycine release from inhibitory spinal cord synapses involved in the regulation of muscle length and tension

  • It causes:
    • Inhibition of stretch reflexes leading to severe muscle spasm
    • Autonomic dysfunction and tissue destruction (2' to exotoxin tetanolysin)

Botulinum toxins

  • A group of toxins (A, B, C1, D, E and F) secreted by Clostridium botulinum
  • Of these, A is the most commonly implicated in humans
  • Cleaves and therefore disrupts SNARE proteins involved in the fusion of ACh-containing vesicles at the pre-synaptic membrane
  • This effectively prevents acetylcholine release pre-synaptically
  • Causes a flaccid paralysis

  • Hemicholinium is a synthetic molecule that blocks re-uptake of choline into nerve endings
  • This reduces choline availability for acetylcholine synthesis and therefore reduces NMJ transmission