19A17: Exam Report

Explain the physiology of neuromuscular transmission.

60% of candidates passed this question.

Description of sequential events from axon conduction to detail at the neuromuscular junction was required. Well-constructed answers defined neuromuscular transmission, elucidated the structure of the neuromuscular junction (best done with a detailed diagram), described the central importance of acetylcholine, including synthesis, storage, receptors, and degradation. An ideal answer also described both pre-synaptic (e.g. voltage-gated calcium channels, exocytosis of vesicles) and post-synaptic events (acetylcholine receptors, end plate potentials, and the events that lead to excitation-contraction coupling in skeletal muscle).

L1ii / 19A17: Explain the physiology of neuromuscular transmission

Definition

  • NMJ = interface between nervous system & skeletal m.
  • NT = ACh
  • Skeletal m. innervated by Aα motor neuron
  • Aa = large diameter, myelinated, arise from anterior horn SC
  • At muscle, Aα axon divides into branches
    • Each axon forms a single junction with a muscle fibre
    • 1 group muscle fibres innervated by 1 motor n. = MOTOR UNIT
    • Each Aα motor n. can innervate 1 – 2000 muscle fibres
    • But each muscle fibre only supplied by 1 Aα motor n.

Anatomy

  • Aα motor n. approaches muscle → loses myelin & branches into ‘Terminal Buttons’
  • Muscle membrane opp Terminal Button is invaginated to form JUNCTIONAL FOLDS
  • NAChR is at the top of fold → Anti-cholinesterase enzymes located in valley of folds
  • Space b/w Motor End Plate & Terminal Button KA JUNCTIONAL CLEFT
Anatomy

ACh Synthesis & Release

  • Nerve cytoplasm: Acetyl CoA + choline → ACh
  • 80% stored in vesicles, 20% stored in cytoplasm
  • ACh vesicles transported to NMJ
    • AP arrives at Terminal Button
    • Ca2+ influx at presynaptic terminal
    • Vesicle fuses with membrane
    • Releases contents into NMJ
    • Delayed opening K+ channel then restores membrane potential

NAChR & Events Leading To E-C-C

  • 5 units: 2 α, β, γ
  • One ACh binds 2 x subunits (+ve cooperativity)
  • Channel opens = ↑ permeability to cations (Na, K, Mg)
  • Na+ INFLUX (biggest flux), K+ OUTFLOW (down their [ ] gradient)
  • Allow depol. of sarcolemma which allows an End Plate Potential (EPP) of -55mV to be reached
  • Reaching EPP allows AP to propagate along entire sarcolemma (i.e. muscle AP)
  • The AP propagated along sarcolemma → down T tubules

→ Activates DIHYDROPYRIDINE RECEPTORS (voltage gated Ca2+ channels)

→ Ca2+ released → further ↑Ca2+ from adjacent RYANODINE RECEPTORS → mass ↑↑↑Ca2+ intracellularly

Motor Nerve Action Potential

  • Motor n. RMP -90mV
  • 2 types depolarisation because 2 types ACh release:

1. Spontaneous ACh Release

  • Vesicles in Terminal Button randomly fuse with presynaptic membrane
  • Release ACh into Synaptic Celft
  • Small electrical 1mV charge
  • KA Miniature End Plate Potential (MEPP)

2. Mass ACh Release

  • Arrival of AP to Terminal Button
  • Ca2+ influx presynaptic terminal
  • 200 vesicles, containing 1500 ACh each, released into Synaptic Cleft
  • Depolarises post-synaptic membrane 50 – 75mV
  • Results in End Plate Potential (EPP)

NB: Each nerve releases x 10 amount of ACh needed → margin of safety for normal neuromuscular transmission

ACh Removal

  • Acetylcholinesterase (AChE) living in junctional folds
ACh Removal

Neuromuscular Blockade

  • Block ACh Synthesis → HEMICHOLINIUM
  • Deplete ACh Stores → TETANUS TOXIN
  • ↑MEPP Frequency & deplete ACh stores
    • THEOPHYLLINE
    • DIGOXIN
    • CATECHOLAMINES
  • Prevent ACh release
    • BOTULINUM TOXIN
    • Local anaesthetic
    • Mg2++
    • AMINOGLYCOSIDE ANTIBIOTICS

 

  • Block ACh Receptors