MSK – NMJ

Master answer

Neuromuscular Transmission

• In nerve cells, a reduction in cell membrane potential above RMP (ie. – 70mV) results in a voltage dependent increase in Na+ permeability.
• the wave of excitation moves along the axon unidirectionally at a constant amplitude & velocity.
• At the neuromuscular junction presynaptic motor axons terminate 30 nanometers from the cell membrane or sarcolemma of a muscle fiber.
• The sarcolemma at the junction has invaginations called postjunctional folds, which increase its surface area facing the synaptic cleft.
• These postjunctional folds form the motor endplate, which is studded with nicotinic acetylcholine receptors (nAChRs)

Neuromuscular Junction

Acetyl Choline:

• stored in vesicles within the terminal button
• approx. 10,000 molecules in each vesicle
• 3 pools (1% immediately releasable, 80% readily releasable, rest stationary store)
• Ach inhibits Choline Acetyltransferase

• Vesicles exocytose in response to depolarization of presynaptic terminal and influx of calcium
• Acetylcholine released into the synaptic cleft
• Pyruvate in Mitochondria → Acetyl-CoA
• Choline – 50% from extracellular (diet) + 50% recycled from Ach

ACh Receptor

• Nicotinic subtype
• 5 polypeptide subunits – ring structure with central pore
• Two α (Bind ACh), One β, One g, One δ
• Locations:
  • Post junctional membrane receptors on motor end plate
  • Extra-junctional
  • Pre-junctional

Activation:

• Ach bind to alpha subunits → opens the ion gated channed
• Movement of all cations, but mainly sodium → depolarizes membrane
• Once reaches threshold of -50mV (from resting of -80) → voltage gated sodium channels open → rapid depolarization → end plate potential (EPP) of 50-100mV
• This triggers muscle action potential → muscle contraction
• Muscle AP propogates along muscle membrane to cause contraction
• Pre-junctional receptors → positive feedback → increased Ach by second messenges system
  • Play role in “fade” seen in non-depolarizing muscle blockers

Fate:

• Acetyl choline hydrolysed to choline and acetate by AChE (Acetyl Choline Esterase)
• Breakdown is very rapid, so the inward current through receptor is transient, followed by rapid repolarisation to resting state

Sources:
AnaesthesiaUK
Arthur Karlin, Nicotinic Acetylcholine receptors, Nature reviews Neuroscience

JC 2019

Answer by JC