Synaptotagmin-7 is a principal Ca2+ sensor for Ca2+-induced glucagon exocytosis in pancreas

• Published in: The Journal of physiology Vol. 587; no. 6; pp. 1169 - 1178
• Main Authors: Gustavsson, Natalia, Wei, Shun‐Hui, Hoang, Dong Nhut, Lao, Ye, Zhang, Quan, Radda, George K., Rorsman, Patrik, Südhof, Thomas C., Han, Weiping
• Format: Journal Article
• Language: English
• Published: Oxford, UK The Physiological Society 15.03.2009; Blackwell Publishing Ltd; Blackwell Science Inc
• Subjects: Action Potentials - physiology; Animals; Blood Glucose - drug effects; Calcium Channels - metabolism; Cellular; Exocytosis - drug effects; Exocytosis - physiology; Gene Expression - genetics; Glucagon - blood; Glucagon - genetics; Glucagon - pharmacology; Glucagon - secretion; Glucagon-Secreting Cells - metabolism; Glucagon-Secreting Cells - secretion; Glucagon-Secreting Cells - ultrastructure; Hypoglycemia - blood; Insulin - pharmacology; Intracellular Calcium-Sensing Proteins - physiology; Islets of Langerhans - secretion; Male; Mice; Mice, Inbred Strains; Mice, Knockout; omega-Conotoxins - pharmacology; Synaptotagmins - physiology
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2008.168005

Hormones such as glucagon are secreted by Ca 2+ -induced exocytosis of large dense-core vesicles, but the mechanisms involved have only been partially elucidated. Studies of pancreatic β-cells secreting insulin revealed that synaptotagmin-7 alone is not sufficient to mediate Ca 2+ -dependent insulin granule exocytosis, and studies of chromaffin cells secreting neuropeptides and catecholamines showed that synaptotagmin-1 and -7 collaborate as Ca 2+ sensors for exocytosis, and that both are equally involved. As no other peptide secretion was analysed, it remains unclear whether synaptotagmins generally act as Ca 2+ sensors in large dense-core vesicle exocytosis in endocrine cells, and if so, whether synaptotagmin-7 always functions with a partner in that role. In particular, far less is known about the mechanisms underlying Ca 2+ -triggered glucagon release from α-cells than insulin secretion from β-cells, even though insulin and glucagon together regulate blood glucose levels. To address these issues, we analysed the role of synaptotagmins in Ca 2+ -triggered glucagon exocytosis. Surprisingly, we find that deletion of a single synaptotagmin isoform, synaptotagmin-7, nearly abolished Ca 2+ -triggered glucagon secretion. Moreover, single-cell capacitance measurements confirmed that pancreatic α-cells lacking synaptotagmin-7 exhibited little Ca 2+ -induced exocytosis, whereas all other physiological and morphological parameters of the α-cells were normal. Our data thus identify synaptotagmin-7 as a principal Ca 2+ sensor for glucagon secretion, and support the notion that synaptotagmins perform a universal but selective function as individually acting Ca 2+ sensors in neurotransmitter, neuropeptide, and hormone secretion.