Abstract
The neuromuscular synapse is a relatively large synapse with hundreds of active zones in presynaptic motor nerve terminals and more than ten million acetylcholine receptors (AChRs) in the postsynaptic membrane. The enrichment of proteins in presynaptic and postsynaptic membranes ensures a rapid, robust, and reliable synaptic transmission. Over fifty years ago, classic studies of the neuromuscular synapse led to a comprehensive understanding of how a synapse looks and works, but these landmark studies did not reveal the molecular mechanisms responsible for building and maintaining a synapse. During the past two-dozen years, the critical molecular players, responsible for assembling the specialized postsynaptic membrane and regulating nerve terminal differentiation, have begun to be identified and their mechanism of action better understood. Here, we describe and discuss five of these key molecular players, paying heed to their discovery as well as describing their currently understood mechanisms of action. In addition, we discuss the important gaps that remain to better understand how these proteins act to control synaptic differentiation and maintenance.
Highlights
Studies by Katz and colleagues established the fundamental mechanisms for synaptic transmission [1]
Despite the absence of myofibers, regenerating motor axons returned selectively to the original synaptic sites, where they differentiated and formed active zones [5]. These studies indicated that factors, which were stably maintained within the synaptic basal lamina, could control the differentiation of motor nerve terminals
Much remains unknown: how does ACh stimulate Calpain activity; how does Rapsyn reduce Calpain activity; how does Agrin stimulate recruitment of Calpain to Rapsyn; does ACh alter the association between Calpain and Rapsyn; does Calpain have substrates other than p25/Cdk5, such as links between acetylcholine receptors (AChRs)/Rapsyn and a cytoskeleton, which could disperse AChR clusters? because manipulating Calpain activity has a modest effect on dispersal of AChR clusters, additional pathways may act downstream from ACh to disassemble AChR clusters that are not contacted by nerve terminals and stabilized by Agrin
Summary
Studies by Katz and colleagues established the fundamental mechanisms for synaptic transmission [1]. Following propagation of an action potential into the nerve terminal, an influx of calcium stimulates synaptic vesicles, containing ACh, to fuse with the presynaptic membrane, releasing ACh into the synaptic cleft. ACh binds to densely clustered AChRs in the muscle membrane, ensuring for rapid, robust and reliable synaptic transmission. The ligand-gated opening of AChR channels causes focal depolarization of the muscle, which initiates a muscle action potential that triggers muscle contraction. Following the studies by Katz and colleagues, critical molecules for building the neuromuscular synapse and concentrating AChRs in the postsynaptic membrane were identified. Five of these key proteins are discussed here (Figure 1).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
