Regulation of acetylcholine receptor trafficking in neuromuscular development and disease

Abstract

Synapses are specialized cell membrane domains that facilitate neuronal communication. The nerve-muscle synapse, neuromuscular junction (NMJ), has been considered as the best model for the study of synaptogenesis due to its large size, simplicity and accessibility. In the postsynaptic membrane, acetylcholine receptors (AChRs) are highly concentrated for effective communication between presynaptic and postsynaptic cells. Over the past decades, a significant progress has been made to understand the signaling molecules and their signaling pathways involved in the anchoring and clustering of AChRs in the postsynaptic membrane at developing NMJs. However, the mechanisms underlying the dynamic trafficking of AChRs to/from the postsynaptic membrane remain unclear. Using Xenopus primary culture system together with molecular manipulation techniques, we found that actin depolymerizing factor (ADF)/cofilin regulated actin-dependent vesicular trafficking of AChRs to the postsynaptic membrane. Active ADF/cofilin was concentrated in small puncta adjacent to AChR clusters and was spatiotemporally correlated with the formation and maintenance of surface AChR clusters. Furthermore, during the pathogenic mechanisms of AChR endocytosis in myasthenia gravis, the disappearance of ADF/cofilin was closely correlated to the disassembly of AChR clusters induced by the treatment of pathogenic antibodies. Taken together, our results have revealed that spatiotemporally restricted ADF/cofilin-mediated actin dynamics regulate AChR trafficking during the assembly and disassembly of neuromuscular synapses in development and disease, respectively.