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

Natalia Gustavsson, Ye Lao, Anton Maximov, Jen Chieh Chuang, Elena Kostromina, Joyce J. Repa, Cai Li, George K. Radda, Thomas C. Südhof, Weiping Han

Research output: Contribution to journalArticle

119 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)3992-3997
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number10
DOIs
StatePublished - Mar 25 2008

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Synaptotagmins
Glucose Intolerance
Insulin
Synaptotagmin II
Calcium
Synaptotagmin I
Glucose
Exocytosis
Secretory Vesicles
Tissue Distribution
Transducers
Synaptic Transmission
Neurotransmitter Agents
Insulin Resistance
Vertebrates
Maintenance

Keywords

  • Calcium sensor
  • Exocytosis
  • Glucose tolerance
  • Insulin sensitivity
  • NADH

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Impaired insulin secretion and glucose intolerance in synaptotagmin-7 null mutant mice. / Gustavsson, Natalia; Lao, Ye; Maximov, Anton; Chuang, Jen Chieh; Kostromina, Elena; Repa, Joyce J.; Li, Cai; Radda, George K.; Südhof, Thomas C.; Han, Weiping.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 10, 25.03.2008, p. 3992-3997.

Research output: Contribution to journalArticle

Gustavsson, N, Lao, Y, Maximov, A, Chuang, JC, Kostromina, E, Repa, JJ, Li, C, Radda, GK, Südhof, TC & Han, W 2008, 'Impaired insulin secretion and glucose intolerance in synaptotagmin-7 null mutant mice', Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 10, pp. 3992-3997. https://doi.org/10.1073/pnas.0711700105
Gustavsson, Natalia ; Lao, Ye ; Maximov, Anton ; Chuang, Jen Chieh ; Kostromina, Elena ; Repa, Joyce J. ; Li, Cai ; Radda, George K. ; Südhof, Thomas C. ; Han, Weiping. / Impaired insulin secretion and glucose intolerance in synaptotagmin-7 null mutant mice. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 10. pp. 3992-3997.
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