Chapter 12 Regulation of Membrane Protein Organization at the Neuromuscular Junction

Abstract

Publisher Summary This chapter discusses the regulation of membrane-protein organization at the neuromuscular junction. Agrin is an extracellular-matrix protein released by the motor neuron at the time of synapse formation. It resides in the synaptic cleft of the neuromuscular junction (NMJ), where it forms part of the stable basal lamina. In this location, agrin induces the formation of Ach receptor (AchR) clusters under the nerve-muscle synapse. The underlying molecular mechanisms of agrin's actions are likely to involve tethering AChR to the cytoskeleton. Several lines of evidence support this hypothesis. First, agrin induces cluster formation by redistributing AChR already present on the muscle-cell membrane and has no effect on AchR-subunit synthesis. Second, AChR clusters are more resistant to detergent extraction than unclustered receptors. Third, many spectrin-like molecules, including syntrophin, utrophin, p-spectrin, the 87-kDa protein, and rapsyn, are specifically co-localized with AChRs at the NMJ. These molecules are likely to serve as a link between AChRs and the actin cytoskeleton. Agrin binds to α-dystroglycan (DG), a glycoprotein complex (GC) member. The GC is linked to the cytoskeleton by binding dystrophin or utrophin, spectrin-like proteins known to bind F-actin. These data provide a model in which agrin, by binding to a-DG, traps the AChRs as they diffuse into the agrin-receptorcytoskeleton complex.