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

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124 Scopus citations

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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Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Gustavsson, N., Lao, Y., Maximov, A., Chuang, J. C., Kostromina, E., Repa, J. J., Li, C., Radda, G. K., Südhof, T. C., & 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, 105(10), 3992-3997. https://doi.org/10.1073/pnas.0711700105