TY - JOUR

T1 - Synaptotagmin-7 phosphorylation mediates GLP-1-dependent potentiation of insulin secretion from β-cells

AU - Wu, Bingbing

AU - Wei, Shunhui

AU - Petersen, Natalia

AU - Ali, Yusuf

AU - Wang, Xiaorui

AU - Bacaj, Taulant

AU - Rorsman, Patrik

AU - Hong, Wanjin

AU - Südhof, Thomas C

AU - Han, Weiping

PY - 2015/8/11

Y1 - 2015/8/11

N2 - 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.

AB - 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.

KW - Amino Acid Sequence

KW - Animals

KW - Colforsin

KW - Conserved Sequence

KW - Cyclic AMP

KW - Cyclic AMP-Dependent Protein Kinases

KW - Evolution, Molecular

KW - Exocytosis

KW - Glucagon-Like Peptide 1

KW - Glucagon-Like Peptide-1 Receptor

KW - Glucose

KW - HEK293 Cells

KW - Humans

KW - Insulin

KW - Insulin-Secreting Cells

KW - Mice, Knockout

KW - Molecular Sequence Data

KW - Mutation

KW - Peptides

KW - Phosphorylation

KW - Phosphoserine

KW - Rats

KW - Receptors, Glucagon

KW - Synaptotagmins

KW - Venoms

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1073/pnas.1513004112

DO - 10.1073/pnas.1513004112

M3 - Journal article

C2 - 26216970

VL - 112

SP - 9996

EP - 10001

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 32

ER -