nihms132899f1

The normal NMJ and pathophysiology of MG: (A) Components of the NMJ. In the normal NMJ, ACh is released from the nerve terminal following a nerve action potential, and interacts with the AChR on the postsynaptic membrane. Voltage-gated Ca2+ channels allow the influx of Ca2+ into the nerve terminal, which facilitates the release of ACh. Voltage-gated Na+ channels on the postsynaptic membrane serve to propagate the muscle action potential on depolarisation. Acetylcholinesterase scavenges and hydrolyses unbound ACh. MUSK initiates clustering of the cytoplasmic protein rapsyn and AChRs, and is believed to maintain normal postsynaptic architecture. (B) Effect of the loss of functional AChRs in MG. Conceptual representation of EPP amplitudes after repeated nerve stimulation. EPP amplitude is reduced in MG, narrowing the safety factor of neuromuscular transmission. With repeated stimulations, the EPP amplitude falls below threshold (indicated by the dotted line) for muscle fibre activation, resulting in neuromuscular transmission failure. (C) Electron micrographs of endplate regions from mice with experimental MG, showing lysis and altered morphology of the postsynaptic membrane. A normal endplate region is shown in the left panel. An endplate region from a myasthenic mouse showing loss of normal endplate morphology due to complement-mediated lysis is shown in the right panel. Postsynaptic membranes are indicated by the arrows. | ACh=acetylcholine. AChR=ACh receptor. EPP=endplate potential. MG=myasthenia gravis. MUSK=muscle-specific receptor tyrosine kinase. NMJ=neuromuscular junction. NT=nerve terminal. | Meriggioli, M. N., & Sanders, D. B. (2009). Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. The Lancet. Neurology, 8(5), 475–490. https://doi.org/10.1016/S1474-4422(09)70063-8

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