Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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 publication

DOI

10.1073/pnas.1513004112

Type

Journal article

Journal

Proc Natl Acad Sci U S A

Publication Date

11/08/2015

Volume

112

Pages

9996 - 10001

Keywords

diabetes, exocytosis, incretin, phosphorylation, synaptotagmin, 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