Impaired insulin secretion and glucose intolerance in synaptotagmin-7 null mutant mice

• Published in: Proceedings of the National Academy of Sciences - PNAS 2008-03, Vol.105 (10), p.3992-3997
• Main Authors: Gustavsson, Natalia, Lao, Ye, Maximov, Anton, Chuang, Jen-Chieh, Kostromina, Elena, Repa, Joyce J, Li, Cai, Radda, George K, Südhof, Thomas C, Han, Weiping
• Format: Article
• Language: English
• Subjects: Adipose Tissue - drug effects; Animals; Beta cells; Biological Sciences; Body Weight - drug effects; Calcium; Calcium Signaling - drug effects; Cellular biology; Exocytosis; Female; Gene expression regulation; Glucose; Glucose - metabolism; Glucose - pharmacology; Glucose Intolerance - metabolism; Insulin; Insulin - metabolism; Insulin resistance; Insulin Secretion; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - ultrastructure; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Mutation; NADP - metabolism; Rodents; Sensors; Synaptotagmins; Synaptotagmins - deficiency; Synaptotagmins - metabolism; Type 2 diabetes mellitus; Vertebrates
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0711700105

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 Ca²⁺ transducers regulating other Ca²⁺-dependent membrane processes, such as insulin secretion in pancreatic β-cells. Of these other synaptotagmins, synaptotagmin-7 is one of the most abundant and is present in pancreatic β-cells. To determine whether synaptotagmin-7 regulates Ca²⁺-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 β cells.