Figure 10.

Schematic summary of the observed effects of rapsyn treatment in control and EAMG muscles. A: In untreated control muscles of young rats, the AChR is clustered densely but anchored incompletely to the cytoskeleton because of the low synaptic expression of rapsyn. Extrasynaptic rapsyn expression possibly contributes to the endplate maintenance (see Discussion). B: In rapsyn-treated controls, rapsyn anchors the AChR tightly to the cytoskeleton via the utrophin-dystroglycan complex. Extrasynaptic rapsyn accumulates in the cell membrane and is partially transported to the synapse. C: In untreated EAMG muscles, anti-AChR antibodies damage the postsynaptic membrane. AChR, rapsyn, and utrophin are degraded and the postsynaptic folding is reduced. Extrasynaptically, AChR is up-regulated as a consequence of functional denervation. The increased extrasynaptic AChR level helps to replace lost AChR at the endplate. D: In rapsyn-treated EAMG muscles, rapsyn and AChR co-localize both synaptically as well as extrasynaptically. Rapsyn increases the AChR clustering in the postsynaptic membrane, but the damage to the utrophin-dystroglycan complex prevents AChR anchoring to the cytoskeleton. Therefore, the newly clustered AChR is susceptible to antigenic modulation by antibodies and is internalized by endocytosis. The increased antibody binding and AChR turnover leads to an aggravation of the ultrastructural damage of the postsynaptic membrane. Moreover, extrasynaptic AChR clustering induced by rapsyn overexpression prevents AChR trafficking to the perisynaptic area and the replacement of lost AChR.