title: Synaptotagmin-7 phosphorylation mediates GLP-1-dependent potentiation of insulin secretion from β-cells.
abstract: 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.
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research, Singapore 138667, Republic of Singapore;
authors.forename: Bingbing
authors.initials: B
authors.lastname: Wu
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research, Singapore 138667, Republic of Singapore;
authors.forename: Shunhui
authors.initials: S
authors.lastname: Wei
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research, Singapore 138667, Republic of Singapore;
authors.forename: Natalia
authors.initials: N
authors.lastname: Petersen
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research, Singapore 138667, Republic of Singapore;
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Ali
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research, Singapore 138667, Republic of Singapore;
authors.forename: Xiaorui
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305;
authors.forename: Taulant
authors.initials: T
authors.lastname: Bacaj
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Headington OX3 7LE, United Kingdom;
authors.forename: Patrik
authors.initials: P
authors.lastname: Rorsman
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore 138673, Republic of Singapore.
authors.forename: Wanjin
authors.initials: W
authors.lastname: Hong
authors.affiliation: Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305; tcs1@stanford.edu weiping_han@sbic.a-star.edu.sg.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
authors.affiliation: Singapore Bioimaging Consortium, Agency for Science, Technology and Research, Singapore 138667, Republic of Singapore; tcs1@stanford.edu weiping_han@sbic.a-star.edu.sg.
authors.forename: Weiping
authors.initials: W
authors.lastname: Han
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D017124:Conserved Sequence; D000242:Cyclic AMP / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D019143:Evolution, Molecular; D000077270:Exenatide; D005089:Exocytosis / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010455:Peptides / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D051381:Rats; D018027:Receptors, Glucagon / Q000378:metabolism; D050857:Synaptotagmins / Q000737:chemistry / Q000378:metabolism*; D014688:Venoms / Q000494:pharmacology
chemical_list: C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D050857:Synaptotagmins; D010768:Phosphoserine; D005576:Colforsin; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose
keywords: diabetes; exocytosis; incretin; phosphorylation; synaptotagmin