Basic physiology of Neuromuscular junction

 Macro-anatomy of neuron

  • Motor neuron is surrounded by myelin sheath which is formed by the Swann cell. 
  • Speed of conduction in neuron is faster (50 - 100 m/s) due to myelin insulation and node of Ranvier.
  • In the node of Ranvier, there is a high concentration of voltage-gated sodium channel causing depolarisation and saltatory movement to the next node.  
  • The neuromuscular junction commences at the nonmyelinated nerve ending. 
  • Extraocular, laryngeal and some facial muscles are innervated by slow conducting Ɣ neuron with multiple innervations. 

Motor endplate 

  • The axon terminal surrounded by Schwann cell cytoplasm contains mitochondria and vesicles. 
  • The synaptic vesicles are synthesised in the anterior horn cell of the spinal cord and transported to the motor nerve terminal via the micro-tubular system. 
  • The synaptic gap is 50 nm wide and contains a basement lamina of 20 nm consisting of mucopolysaccharides. 
  • Ach receptors are arranged in discrete groups on the shoulders/ crests of the junctional fold. Their density is a maximum of 10,000 µm2. 
  • AchE (acetylcholinesterase) is present in the synaptic gap, firmly attached to the basement membrane by collagen fibres. 
  • Both Ach and AchE are present in the presynaptic nerve terminal. 

Acetylcholine receptor

  • Postsynaptic AchR: 𝛅ε, 𝛅Ɣ, 7; Presynaptic AchR: 3 β2, Ganglia: 3 β4  
  • The amount of acetylcholine released from the presynaptic membrane is regulated by presynaptic AchR, during the high rate of stimulation. 
  • The fade - in neuromuscular monitoring is due to the blockade of the presynaptic receptor.
  • 𝛅ε - is the main site of action of NMBA
  • 𝛅Ɣ - Present during the denervated state and other neuromuscular disease states. Slow onset of action of NMBA and long duration of action. 
  • 7 - Present during denervated state and other neuromuscular disease states. Has a role in the regulation of inflammation. 
  • subunit of postsynaptic receptor has Ach binding site at the interface with 𝛅 and ε subunits. 
  • Activation of the receptor requires both sites to be activated. 


  • At the motor endplate, choline is partly derived from the hydrolysis of Ach and partly from plasma. 
  • The active transport of choline to axoplasm from ECF via neurolemma is the rate-limiting step in the synthesis of Ach by choline acetyltransferase (ChAT). 
  • ChAT is produced in the body of the neuron and is transported to the nerve terminal, where its concentration is highest. The presence of ChAT in a nerve cell classifies this cell as a "cholinergic" neuron.
  • Choline + Acetyl - coenzyme A →  Ach + coenzyme A
  • The synthesis of Ach in axoplasm is increased by its release. 
  • Ach is not depleted by rapid nerve conduction or choline deficiency. 
  • 50% of synthesised Ach is stored in synaptic vesicles as quanta. Each vesicles contains 10,000 - 12,000 of Ach molecules, ATP, Ca2+ and proteoglycans. 
  • Some of the remaining Ach leaks across the axonal membrane and remains in a significant amount in Swann cells and sarcoplasm of muscle fibres. 
  • The spontaneous release of Ach causes miniature end plate potential (MEPP) on the postsynaptic membrane but these are insufficient to produce a muscle action potential. 
  • The amount of Ach release by action potential is termed quantum, the size of quantum is dependent on the number of vesicles docking in the presynaptic membrane and varies on the frequency of nerve stimulation. 
  • One nerve stimulation leads to the release of 200 - 300 vesicles. 
  • Neuromuscular transmission must be rapid and Ach must be removed from the synaptic cleft because it can produce flaccid paralysis by the neuromuscular blockade.
  • Vesicles are attached to the cytoskeletal elements by synapsin 1
  • ⬇️

    Depolarisation → Ca2+ entry → activates CPK (calmodulin-dependent protein kinase) → CPK causes phosphorylation of Synaptin 1 → release of vesicle 


    Vesicle migrates to axonal membrane 


    Vesicular proteins (Synaptotagmin, Synaptobrevin, Synaptophysin)  are bound by a docking site in the membrane 


    Synaptotagmin is stimulated by Ca2+ and causes the release of Ach in the synaptic gap by exocytosis


    Released Ach bind to subunit of AchR and causes Na+ influx (end plate current), followed by an efflux of K+. The summation of this current through a large number of receptors generates depolarisation of 40 mV. 


    When end plate potential reaches this critical threshold (from - 90 mV to - 50 mV), a muscle action potential is generated and propagated along the muscle fibres. 


    Muscle action potential depolarises the T - tubule membrane and activates the dihydropyridine receptor in the membrane 


    This activates the ryanodine receptor in the sarcoplasmic reticulum which causes Ca2+ release 


    Ca2+ binds to Troponin C and causes interaction of actin-myosin

    Presynaptic Calcium channel

    • Presynaptic calcium channels are N-type or P-type (neuronal) and postsynaptic are L - type found in microtubules. 
    • Ach activates the Na+ channel in the pre junctional nerve ending, which in turn activates voltage-gated Ca2+ channel causing a Ca2+ influx to promote further Ach release. 
    • N-type calcium channel is a target of many toxins (e.g. omega conotoxin - is a very potent analgesic and its synthetic analogue Ziconotide is a potent non-opioid, non - NSAID analgesic for intrathecal infusion in chronic pain management)
    • In Lambert - Eaton syndrome, the antibody against the presynaptic calcium channel demonstrates muscle weakness that increases in strength after repeated use. 


    References - 

    • Smith and Aitkenhead's Textbook of Anaesthesia, 7th Edition
    • Pharmacology for Anaesthesia and Intensive Care, 4th Edition 


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