Action Potential Conduction

Snapshot

• A 36-year-old male presents with ascending muscle weakness. The patient is generally healthy, with no pertinent past medical history. He states he recently recovered from diarrhea that has lasted over a week. Neurological examination is notable for weakness in the lower extremities and an abscence of patellar reflexes. (Botulinum toxin)

Introduction

• Action Potential Overview  
  • initiation
    • neuronal membrane potential becomes more positive → opening of voltage gated Na⁺ channels
      • positive feedback loop
      • threshold is reached → action potential generated
  • propagation
    • action potential generated at one portion of neuron → excitation of adjacent neuronal membrane
      • signal thus propagates down the axon via opening of voltage gated Na⁺ channels
  • neuromuscular junction
    • when the propagated action potential reaches the presynaptic neuron, it becomes depolarized
      • this opens voltage gated Ca²⁺ channels
        • allows release of acetylcholine (ACh) from stored vesicles in the presynaptic neuron
    • released ACh act on nicotinic receptors (a ligand-gated ion channel) on the motor end plate
• motor end plate depolarizes, and propagates the action potential down the muscle fiber, ultimately leading to muscle contraction

Action Potential Initiation

• Initiation
  • initial depolarization → opening of voltage gated Na⁺ channels
    • increased Na⁺ inflow → opening of more voltage gated Na⁺ channels (positive feedback loop)
      • threshold is eventually met → action potential generation
    • clinical correlate
      • tetrodotoxin (pufferfish consumption) binds fast voltage-gated Na+ channels in nerve tissue, which does not allow for depolarization or action potential formation
        • can result in nausea, weakness, dizziness or can be fatal
• treatment is supportive

 Action Potential Propagation

• Propagation
  • depolarized region of the neuronal membrane → excitation of adjacent neuronal membrane
  • myelinated neurons
    • Schwann cells myelinates axons of the peripheral nervous system (PNS)
      • myelinates only 1 axon
      • increases conduction velocity 
      • non-myelinated areas are called Nodes of Ranvier
        • contains a high concentration of Na⁺ channels
          • allows “jumping” of action potential from one Node of Ranvier to the next
            • this is saltatory conduction
      • clinical correlate
        • Guillain-Barre syndrome
          • autoimmune destruction of peripheral myelinated neurons
            • classically associated with previous Campylobacter jejuni infection
    • myelinated neuron examples
      • sensory
        • Pacinian corpuscles transmit vibrational sense and pressure via large, myelinated fibers 
  • non-myelinated neurons
    • transmit potentials via Na⁺ channels that exist along the entire length of the axon (no Nodes of Ranvier)
• have same refractory period of Na⁺ channels as myelinated axons do but at a slower velocity of conduction due to lack of insulation (myelin)

Neuromuscular Junction

• Neuromuscular junction 
  • propagated action potential reaches presynaptic neuron → opens voltage gated Ca²⁺ channels
    • clinical correlate
      • Lambert-Eaton syndrome
        • autoantibodies against the presynaptic calcium channels → reduced ACh release → weakness
        • associated with small cell carcinoma of the lung
  • Ca²⁺ influx → ACh release with the help of SNARE proteins
    • clinical correlate
      • botulinum toxin
        • cleaves SNARE proteins → decreased ACh release → flaccid paralysis
      • tetanus toxin
        • cleaves SNARE proteins → decrease release of inhibitory neurotransmitters (GABA and glycine) in the spinal cord → spasticity and overactivity
  • released ACh act on nicotinic receptors (ligand gated ion channels) of the motor end plate
    • clinical correlate
      • myasthenia gravis
        • autoantibodies bind the post-synaptic ACh receptor → weakness
  • depolarization travels along the muscle cell via T-tubules, which are invaginations that allow for the skeletal muscle to be depolarized
  • dihydropyridine receptors are then depolarized
    • mechanically coupled to ryanodine receptors (Ca²⁺ release channels) on the sarcoplasmic reticulum
      • increases intracellular Ca²⁺ concentration → binds to troponin C → cross bridge cycle
        • See Skeletal and Cardiac Muscle Contractions topic 
      • clinical correlate
        • malignant hyperthermia
          • ryanodine or dihydropyridine receptor mutation → unregulated Ca²⁺ release into the muscle cytoplasm → sustained muscle contraction → increased aerobic metabolism → depletion of O2, ATP, and increased CO2 production and acidosis
          • treatment: dantrolene