title: Synaptotagmin-7 is a principal Ca2+ sensor for Ca2+ -induced glucagon exocytosis in pancreas.
abstract: 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.
authors.affiliation: Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, A*STAR, Singapore 138667.
authors.forename: Natalia
authors.initials: N
authors.lastname: Gustavsson
authors.forename: Shun-Hui
authors.initials: SH
authors.lastname: Wei
authors.forename: Dong Nhut
authors.initials: DN
authors.lastname: Hoang
authors.forename: Ye
authors.initials: Y
authors.lastname: Lao
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhang
authors.forename: George K
authors.initials: GK
authors.lastname: Radda
authors.forename: Patrik
authors.initials: P
authors.lastname: Rorsman
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
authors.forename: Weiping
authors.initials: W
authors.lastname: Han
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D015220:Calcium Channels / Q000378:metabolism; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology*; D015870:Gene Expression / Q000235:genetics; D005934:Glucagon / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D050416:Glucagon-Secreting Cells / Q000378:metabolism* / Q000648:ultrastructure; D007003:Hypoglycemia / Q000097:blood; D007328:Insulin / Q000494:pharmacology; D052139:Intracellular Calcium-Sensing Proteins / Q000502:physiology*; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D050857:Synaptotagmins / Q000502:physiology*; D020960:omega-Conotoxins / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D015220:Calcium Channels; D007328:Insulin; D052139:Intracellular Calcium-Sensing Proteins; C494303:Syt7 protein, mouse; D020960:omega-Conotoxins; D050857:Synaptotagmins; D005934:Glucagon