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

J Physiol. 2009 Mar 15;587(Pt 6):1169-78. doi: 10.1113/jphysiol.2008.168005. Epub 2009 Jan 26.


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 beta-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 alpha-cells than insulin secretion from beta-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 alpha-cells lacking synaptotagmin-7 exhibited little Ca(2+)-induced exocytosis, whereas all other physiological and morphological parameters of the alpha-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology
  • Animals
  • Blood Glucose / drug effects
  • Calcium Channels / metabolism
  • Exocytosis / drug effects
  • Exocytosis / physiology*
  • Gene Expression / genetics
  • Glucagon / blood
  • Glucagon / genetics
  • Glucagon / metabolism*
  • Glucagon / pharmacology
  • Glucagon-Secreting Cells / metabolism*
  • Glucagon-Secreting Cells / ultrastructure
  • Hypoglycemia / blood
  • Insulin / pharmacology
  • Intracellular Calcium-Sensing Proteins / physiology*
  • Islets of Langerhans / metabolism
  • Male
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Synaptotagmins / physiology*
  • omega-Conotoxins / pharmacology


  • Blood Glucose
  • Calcium Channels
  • Insulin
  • Intracellular Calcium-Sensing Proteins
  • Syt7 protein, mouse
  • omega-Conotoxins
  • Synaptotagmins
  • Glucagon