title: Impaired insulin secretion and glucose intolerance in synaptotagmin-7 null mutant mice.
abstract: Vertebrates express at least 15 different synaptotagmins with the same domain structure but diverse localizations and tissue distributions. Synaptotagmin-1,-2, and -9 act as calcium sensors for the fast phrase of neurotransmitter release, and synaptotagmin-12 acts as a calcium-independent modulator of release. The exact functions of the remaining 11 synaptotagmins, however, have not been established. By analogy to the role of synaptotagmin-1, -2, and -9 in neurotransmission, these other synaptotagmins may serve as Ca(2+) transducers regulating other Ca(2+)-dependent membrane processes, such as insulin secretion in pancreatic beta-cells. Of these other synaptotagmins, synaptotagmin-7 is one of the most abundant and is present in pancreatic beta-cells. To determine whether synaptotagmin-7 regulates Ca(2+)-dependent insulin secretion, we analyzed synaptotagmin-7 null mutant mice for glucose tolerance and insulin release. Here, we show that synaptotagmin-7 is required for the maintenance of systemic glucose tolerance and glucose-stimulated insulin secretion. Mutant mice have normal insulin sensitivity, insulin production, islet architecture and ultrastructural organization, and metabolic and calcium responses but exhibit impaired glucose-induced insulin secretion, indicating a calcium-sensing defect during insulin-containing secretory granule exocytosis. Taken together, our findings show that synaptotagmin-7 functions as a positive regulator of insulin secretion and may serve as a calcium sensor controlling insulin secretion in pancreatic beta cells.
authors.affiliation: Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, Agency for Science, Technology, and Research (ASTAR), Singapore.
authors.forename: Natalia
authors.initials: N
authors.lastname: Gustavsson
authors.forename: Ye
authors.initials: Y
authors.lastname: Lao
authors.forename: Anton
authors.initials: A
authors.lastname: Maximov
authors.forename: Jen-Chieh
authors.initials: JC
authors.lastname: Chuang
authors.forename: Elena
authors.initials: E
authors.lastname: Kostromina
authors.forename: Joyce J
authors.initials: JJ
authors.lastname: Repa
authors.forename: Cai
authors.initials: C
authors.lastname: Li
authors.forename: George K
authors.initials: GK
authors.lastname: Radda
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
authors.forename: Weiping
authors.initials: W
authors.lastname: Han
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects; D005260:Female; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D018149:Glucose Intolerance / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009249:NADP / Q000378:metabolism; D050857:Synaptotagmins / Q000172:deficiency* / Q000378:metabolism
chemical_list: D007328:Insulin; D050857:Synaptotagmins; D009249:NADP; D005947:Glucose