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The Journal of Neuroscience, February 13, 2008, 28(7):1688-1696; doi:10.1523/JNEUROSCI.4130-07.2008

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Cellular/Molecular
Muscle-Specific Receptor Tyrosine Kinase Endocytosis in Acetylcholine Receptor Clustering in Response to Agrin

Dan Zhu,¹ Zhihua Yang,¹ Zhenge Luo,² Shiwen Luo,¹ Wen C. Xiong,¹ and Lin Mei¹

¹Program of Developmental Neurobiology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, Georgia 30912, and ²Institute of Neuroscience and Key Laboratory of Neurobiology, Shanghai Institutes for Biological Scineces, Chinese Academy of Sciences, Shanghai 200031, China

Correspondence should be addressed to Lin Mei, Program of Developmental Neurobiology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, CB2803, 1120 15th Street, Augusta, GA 30912. Email: lmei{at}mcg.edu

Agrin, a factor used by motoneurons to direct acetylcholine receptor (AChR) clustering at the neuromuscular junction, initiates signal transduction by activating the muscle-specific receptor tyrosine kinase (MuSK). However, the underlying mechanisms remain poorly defined. Here, we demonstrated that MuSK became rapidly internalized in response to agrin, which appeared to be required for induced AChR clustering. Moreover, we provided evidence for a role of N-ethylmaleimide sensitive factor (NSF) in regulating MuSK endocytosis and subsequent signaling in response to agrin stimulation. NSF interacts directly with MuSK with nanomolar affinity, and treatment of muscle cells with the NSF inhibitor N-ethylmaleimide, mutation of NSF, or suppression of NSF expression all inhibited agrin-induced AChR clustering. Furthermore, suppression of NSF expression and NSF mutation attenuate MuSK downstream signaling. Our study reveals a potentially novel mechanism that regulates agrin/MuSK signaling cascade.

Key words: neuromuscular junction; nicotinic acetylcholine receptors; agrin; endocytosis; MuSK; NSF

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Received Sept. 9, 2007; revised Dec. 6, 2007; accepted Dec. 10, 2007.

Correspondence should be addressed to Lin Mei, Program of Developmental Neurobiology, Institute of Molecular Medicine and Genetics, Medical College of Georgia, CB2803, 1120 15th Street, Augusta, GA 30912. Email: lmei{at}mcg.edu

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