On July 19th, Neuron published an article from ION entitled “Rapsyn Interaction with Calpain Stabilizes AChR Clusters at the Neuromuscular Junction”. This study was conducted in the Laboratory of Synaptic Signaling, mainly by graduate students Fei Chen and Lei Qian under the supervision of Dr. Zhen-Ge Luo.

Neuromuscular synapses are formed between motor neurons and skeletal muscle fibers. AChRs are concentrated at the postsynaptic membrane, which guarantees efficient and accurate neurotransmission. AChR clustering is a dynamic process, whereby nascent clusters underneath nerve terminals are stabilized by agrin, a motor neuron derived glycoprotein, and the AChR-associated protein rapsyn. Meanwhile, motor neurons release negative signals to disperse non-innervated clusters and refine clusters at the synapses. Genetic studies suggest that ACh may serve as a negative signal. Such counteractive interaction leads to eventual dispersal of non-synaptic AChR rich-sites and formation of receptor clusters at the postjunctional membrane. However, the underlying mechanisms are not well understood. Dr.Luo’s group found that calpain, a calcium-dependent protease, is activated by the cholinergic stimulation and is required for induced dispersion of AChR clusters. Interestingly, the AChR-associated protein rapsyn interacts with calpain, in an agrin dependent manner, and this interaction inhibits the protease activity of calpain. Disrupting the endogenous rapsyn/calpain interaction enhances CCh-induced dispersion of AChR clusters. Moreover, the loss of AChR clusters in agrin mutant mice was partially rescued by the inhibition of calpain via over-expressing calpastatin, an endogenous calpain inhibitor, or injecting calpeptin, a cell-permeable calpain inhibitor. These results identify a critical signaling mechanism by which ACh destabilizes AChR clusters and reveal a novel function of rapsyn in regulating AChR clustering and NMJ formation. The results presented in this paper also provide insight for studies of neuromuscular disorders.

This work was supported by grants from CAS, National Natural Science Foundation of China, Shanghai Science and Technology Development Foundation, “973” Program, and Key State Research Program of China.

Figure legend. ACh activates calpain to destabilize AChR clusters. Agrin increases the interaction of rapsyn with calpain and inhibits calpain activity to stabilize AChR clusters at the NMJ.