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

Hormones such as glucagon are secreted by Ca2+‐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 Ca2+‐dependent insulin granule exocytosis, and studies of chromaffin cells secreting neuropeptides and catecholamines showed that synaptotagmin‐1 and ‐7 collaborate as Ca2+ sensors for exocytosis, and that both are equally involved. As no other peptide secretion was analysed, it remains unclear whether synaptotagmins generally act as Ca2+ 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 Ca2+‐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 Ca2+‐triggered glucagon exocytosis. Surprisingly, we find that deletion of a single synaptotagmin isoform, synaptotagmin‐7, nearly abolished Ca2+‐triggered glucagon secretion. Moreover, single‐cell capacitance measurements confirmed that pancreatic α‐cells lacking synaptotagmin‐7 exhibited little Ca2+‐induced exocytosis, whereas all other physiological and morphological parameters of the α‐cells were normal. Our data thus identify synaptotagmin‐7 as a principal Ca2+ sensor for glucagon secretion, and support the notion that synaptotagmins perform a universal but selective function as individually acting Ca2+ sensors in neurotransmitter, neuropeptide, and hormone secretion.