Pharmacology of Neuromuscular Transmission

The nicotinic AChR contains five subunits arranged radially around a transmembrane ion channel. Antibodies generated in myasthenia gravis are primarily directed against the AChR alpha subunit. These antibodies may bind at or near the acetylcholine binding site, directly preventing acetylcholine binding, or may alter receptor function through other mechanisms, such as increased receptor degradation or complement-mediated receptor lysis. The receptor that is required for NMJ formation is called the MuSK receptor (muscle-specific kinase). MuSK, agrin, and rapsyn are important for clustering of acetylcholine receptors during neuromuscular junction development by allowing binding to the receptor’s skeletal muscle cytoplasmic domain. Agrin binds several other proteins on the surface of muscle, including dystroglycan and laminin. Rapsyn anchors or stabilizes the AChR at synaptic sites linking the receptor to the underlying postsynaptic cytoskeleton.

Acquired MG develops as a result of formation of antibodies primarily to the alpha-1 postsynaptic NMJ immunogenic regions (epitopes). AChR antibodies trigger immune-mediated AChR degradation. The loss of large numbers of functional AChRs decreases the pool of muscle fibers available for depolarization during motor nerve terminal activation. This results in decreased generation of muscle fiber action potentials and subsequent muscle contraction, leading to clinical weakness if large numbers of NMJs are affected.

Many medications have their pharmacologic site of action at the NMJ, subsequently affecting neuromuscular transmission. Several block Ca²⁺ uptake by the nerve terminal, resulting in impaired mobilization of the ACh vesicles and subsequent ACh release. These include calcium channel blockers and heavy metals. Although these agents do not often produce clinically evident NMJ failure in healthy persons, exposure to these medications in patients with a NMJ disease (i.e., myasthenia gravis or Lambert Eaton myasthenic syndrome) may cause clinical exacerbations.

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