Impaired insulin secretion and glucose intolerance in synaptotagmin-7 null mutant mice.
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.
Gustavsson
Natalia
N
Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, Agency for Science, Technology, and Research (ASTAR), Singapore.
Lao
Ye
Y
Maximov
Anton
A
Chuang
Jen-Chieh
JC
Kostromina
Elena
E
Repa
Joyce J
JJ
Li
Cai
C
Radda
George K
GK
Südhof
Thomas C
TC
Han
Weiping
W
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
D007328:Insulin; D050857:Synaptotagmins; D009249:NADP; D005947:Glucose