TY - JOUR
T1 - Impaired insulin secretion and glucose intolerance in synaptotagmin-7 null mutant mice
AU - Gustavsson, Natalia
AU - Lao, Ye
AU - Maximov, Anton
AU - Chuang, Jen Chieh
AU - Kostromina, Elena
AU - Repa, Joyce J.
AU - Li, Cai
AU - Radda, George K.
AU - Südhof, Thomas C.
AU - Han, Weiping
PY - 2008/3/25
Y1 - 2008/3/25
N2 - 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 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 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 β cells.
AB - 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 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 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 β cells.
KW - Calcium sensor
KW - Exocytosis
KW - Glucose tolerance
KW - Insulin sensitivity
KW - NADH
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U2 - 10.1073/pnas.0711700105
DO - 10.1073/pnas.0711700105
M3 - Article
C2 - 18308938
AN - SCOPUS:41649086377
SN - 0027-8424
VL - 105
SP - 3992
EP - 3997
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 10
ER -