Anti-AChR antibodies: Mechanisms of action

Neuromuscular Junction: Normal

• Many NMJs consist of several spot-like synaptic regions 1-5 μm across
• Presynaptic terminal
  • Releases packets or quanta of acetylcholine
  • Spontaneous release rate: 0.1-10 Hz
  • Trigger: Increase in free Ca⁺⁺ in nerve terminal
  • Effect of release on post-synaptic membrane: Miniature endplate potentials (MEPPs)
  • Single nerve impulse
    • Causes release of 1-3 quanta from each presynaptic terminal bouton
    • Release event at a given active zone: Occurs in response to one of ten nerve impulses
    • Number of quanta released at a NMJ: Proportional to NMJ area
    • Frog NMJs: Large; Release 100-200 quanta per impulse
    • Human NMJs: 10x smaller; Release 20 quanta per impulse
    • Each quantum consists of 5,000 to 10,000 molecules of ACh
• Post-synaptic membrane
  • Acetylcholine receptors (AChRs): High concentration
    • AChRs are concentrated at peaks of, & 1/3 of way down, post synaptic folds
    • Density: ~10,000/μm²; Form near crystalline array
  • Voltage-gated sodium channels
    • High density of Na_v1.4 in folded postsynaptic membrane
    • Effect of transmission at human NMJs is amplified
    • Concentrated at base of folds
  • Structrure
    • Highly folded: Especially prominent in humans
    • Opening of folds: Opposite active zones on nerve terminal

Modulation of post-synaptic AChRs by anti-AChR antibodies

Increased AChR degradation

	Anti-AChR antibodies cross-link post-synaptic AChRs
↓
	Cross-linked AChRs are endocytosed more rapidly than normal
↓
	Internalized AChRs are degraded Fewer AChRs remain on the post-synaptic membrane
RESULT: Less efficient neuromuscular transmission

Damage to Post-synaptic Membrane

	Complement binds to the Antibody-AChR complex Membrane-attack complex (MAC) forms on the membrane
↓
	The post-junctional membrane is damaged Fewer post-synaptic membrane folds Reduced numbers of AChRs Widened synaptic cleft
RESULT: Less efficient neuromuscular transmission

Altered AChR function

Blockade of ACh binding site Acquired immune MG: No prominent blockade of ACh binding to AChRs Recurrent arthrogryposis: Blocking antibodies identified Altered AChR channel function Acquired immune MG: No prominent change in AChR ion channel function Acquired Slow Channel syndrome: Antibodies to adult AChR alter AChR ion channel function