期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：32
页码：9996-10001
DOI：10.1073/pnas.1513004112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe present study shows that glucagon-like peptide-1 (GLP-1) potentiates insulin release by inducing the PKA-mediated phosphorylation of synaptotagmin-7 in pancreatic {beta}-cells, thereby documenting that the hormone GLP-1 acts by directly enhancing Ca2+-triggered insulin exocytosis. PKA phosphorylates synaptotagmin-7 at a single serine residue in the linker between the synaptotagmin-7 transmembrane region and its C-terminal C2 domains that bind Ca2+; accordingly, PKA phosphorylation of synaptotagmin-7 enhances insulin secretion without changing the Ca2+ dependence of secretion. The study documents that the efficacy of a synaptotagmin can be modulated by phosphorylation and highlights the importance of synaptotagmin-7 in mediating glucose-stimulated insulin secretion. Given the importance of enhancing {beta}-cell function in the treatment of diabetes, the present findings may offer new pathways for developing future therapeutic strategies. Glucose stimulates insulin secretion from {beta}-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.
