Synaptotagmin-7 phosphorylation mediates GLP-1-dependent potentiation of insulin secretion from β-cells

Bingbing Wu, Shunhui Wei, Natalia Petersen, Yusuf Ali, Xiaorui Wang, Taulant Bacaj, Patrick Rorsman, Wanjin Hong, Thomas C. Südhof, Weiping Han

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63 Citations (Scopus)


Glucose stimulates insulin secretion from β-cells by increasing intracellular Ca2+. Ca2+ then binds to synaptotagmin-7 as a major Ca2+ sensor for exocytosis, triggering secretory granule fusion and insulin secretion. In type-2 diabetes, insulin secretion is impaired; this impairment is ameliorated by glucagon-like peptide-1 (GLP-1) or by GLP-1 receptor agonists, which improve glucose homeostasis. However, the mechanism by which GLP-1 receptor agonists boost insulin secretion remains unclear. Here, we report that GLP-1 stimulates protein kinase A (PKA)-dependent phosphorylation of synaptotagmin- 7 at serine-103, which enhances glucose- and Ca2+-stimulated insulin secretion and accounts for the improvement of glucose homeostasis by GLP-1. A phospho-mimetic synaptotagmin-7 mutant enhances Ca2+-triggered exocytosis, whereas a phospho-inactive synaptotagmin-7 mutant disrupts GLP-1 potentiation of insulin secretion. Our findings thus suggest that synaptotagmin-7 is directly activated by GLP-1 signaling and may serve as a drug target for boosting insulin secretion. Moreover, our data reveal, to our knowledge, the first physiological modulation of Ca2+-triggered exocytosis by direct phosphorylation of a synaptotagmin.

Original languageEnglish
Pages (from-to)9996-10001
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number32
Early online date26 May 2015
Publication statusPublished (in print/issue) - 11 Aug 2015


  • Diabetes
  • Exocytosis
  • Incretin
  • Phosphorylation
  • Synaptotagmin


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