Wu Bingbing, Wei Shunhui, Petersen Natalia, Ali Yusuf, Wang Xiaorui, Bacaj Taulant, Rorsman Patrik, Hong Wanjin, Südhof Thomas C, Han Weiping
Singapore Bioimaging Consortium, Agency for Science, Technology and Research, Singapore 138667, Republic of Singapore;
Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305;
Proc Natl Acad Sci U S A. 2015 Aug 11;112(32):9996-10001. doi: 10.1073/pnas.1513004112. Epub 2015 Jul 27.
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.
葡萄糖通过增加细胞内钙离子浓度来刺激β细胞分泌胰岛素。钙离子随后作为胞吐作用的主要钙离子传感器与突触结合蛋白-7结合，触发分泌颗粒融合和胰岛素分泌。在2型糖尿病中，胰岛素分泌受损；胰高血糖素样肽-1（GLP-1）或GLP-1受体激动剂可改善这种损伤，从而改善葡萄糖稳态。然而，GLP-1受体激动剂促进胰岛素分泌的机制仍不清楚。在此，我们报告GLP-1刺激突触结合蛋白-7的丝氨酸-103位点发生蛋白激酶A（PKA）依赖性磷酸化，这增强了葡萄糖和钙离子刺激的胰岛素分泌，并解释了GLP-1对葡萄糖稳态的改善作用。一种磷酸模拟型突触结合蛋白-7突变体增强了钙离子触发的胞吐作用，而一种磷酸失活型突触结合蛋白-7突变体则破坏了GLP-1对胰岛素分泌的增强作用。因此，我们的研究结果表明，突触结合蛋白-7可被GLP-1信号直接激活，并可能作为促进胰岛素分泌的药物靶点。此外，据我们所知，我们的数据揭示了通过直接磷酸化突触结合蛋白对钙离子触发的胞吐作用进行的首次生理调节。
