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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-08, Vol.112 (32), p.9996-10001
• Main Authors: Wu, Bingbing, Wei, Shunhui, Petersen, Natalia, Ali, Yusuf, Wang, Xiaorui, Bacaj, Taulant, Rorsman, Patrik, Hong, Wanjin, Südhof, Thomas C., Han, Weiping
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Biological Sciences; Colforsin - pharmacology; Conserved Sequence; Cyclic AMP - pharmacology; Cyclic AMP-Dependent Protein Kinases - metabolism; Evolution, Molecular; Exenatide; Exocytosis - drug effects; Glucagon-Like Peptide 1 - metabolism; Glucagon-Like Peptide-1 Receptor; Glucose - pharmacology; HEK293 Cells; Humans; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Mice, Knockout; Molecular Sequence Data; Mutation - genetics; Peptides - pharmacology; Phosphorylation - drug effects; Phosphoserine - metabolism; Rats; Receptors, Glucagon - metabolism; Synaptotagmins - chemistry; Synaptotagmins - metabolism; Venoms - pharmacology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1513004112

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.