Synaptotagmin-7 phosphorylation mediates GLP-1-dependent potentiation of insulin secretion from β-cells
Research output: Contribution to journal › Journal article › Research › peer-review
Glucose stimulates insulin secretion from β-cells by increasing intracellular Ca(2+). Ca(2+) then binds to synaptotagmin-7 as a major Ca(2+) 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 Ca(2+)-stimulated insulin secretion and accounts for the improvement of glucose homeostasis by GLP-1. A phospho-mimetic synaptotagmin-7 mutant enhances Ca(2+)-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 Ca(2+)-triggered exocytosis by direct phosphorylation of a synaptotagmin.
Original language | English |
---|---|
Journal | National Academy of Sciences. Proceedings |
Volume | 112 |
Issue number | 32 |
Pages (from-to) | 9996-10001 |
Number of pages | 6 |
ISSN | 0027-8424 |
DOIs | |
Publication status | Published - 11 Aug 2015 |
- Amino Acid Sequence, Animals, Colforsin, Conserved Sequence, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Evolution, Molecular, Exocytosis, Glucagon-Like Peptide 1, Glucagon-Like Peptide-1 Receptor, Glucose, HEK293 Cells, Humans, Insulin, Insulin-Secreting Cells, Mice, Knockout, Molecular Sequence Data, Mutation, Peptides, Phosphorylation, Phosphoserine, Rats, Receptors, Glucagon, Synaptotagmins, Venoms, Journal Article, Research Support, Non-U.S. Gov't
Research areas
ID: 172512640