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

^†Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, Agency for Science, Technology, and Research (A*STAR), Singapore 138667;
^‡Center for Basic Neuroscience, Howard Hughes Medical Institute and
^§Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75235;
^¶Merck Research Laboratories, Rahway, NJ 07065; and
^††Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597

Communicated by Britton Chance, University of Pennsylvania School of Medicine, Philadelphia, PA, December 15, 2007 (received for review August 23, 2007)

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 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.

Footnotes

^‖To whom correspondence may be addressed. E-mail: thomas.sudhof{at}utsouthwestern.edu or weiping_han{at}sbic.a-star.edu.sg
Author contributions: J.J.R., C.L., G.K.R., T.C.S., and W.H. designed research; N.G., Y.L., A.M., J.-C.C., E.K., and W.H. performed research; N.G., Y.L., A.M., J.-C.C., E.K., and W.H. analyzed data; and N.G., T.C.S., and W.H. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0711700105/DC1.
Freely available online through the PNAS open access option.