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, Patrick
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 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.
AB - 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.
KW - Diabetes
KW - Exocytosis
KW - Incretin
KW - Phosphorylation
KW - Synaptotagmin
UR - http://www.scopus.com/inward/record.url?scp=84938908831&partnerID=8YFLogxK
UR - https://pure.ulster.ac.uk/en/publications/synaptotagmin-7-phosphorylation-mediates-glp-1-dependent-potentia
U2 - 10.1073/pnas.1513004112
DO - 10.1073/pnas.1513004112
M3 - Article
C2 - 26216970
AN - SCOPUS:84938908831
SN - 0027-8424
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
IS - 32
ER -
