Muscle-specific receptor tyrosine kinase endocytosis in acetylcholine receptor clustering in response to agrin

Dan Zhu, Zhihua Yang, Zhenge Luo, Shiwen Luo, Wen C. Xiong, Lin Mei

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1688-1696
Number of pages9
JournalJournal of Neuroscience
Volume28
Issue number7
DOIs
StatePublished - Feb 13 2008

Keywords

  • Agrin
  • Endocytosis
  • MuSK
  • NSF
  • Neuromuscular junction
  • Nicotinic acetylcholine receptors

ASJC Scopus subject areas

  • Neuroscience(all)

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