title: Neuronal calcium sensor synaptotagmin-9 is not involved in the regulation of glucose homeostasis or insulin secretion.
abstract: BACKGROUND
  Insulin secretion is a complex and highly regulated process. It is well established that cytoplasmic calcium is a key regulator of insulin secretion, but how elevated intracellular calcium triggers insulin granule exocytosis remains unclear, and we have only begun to define the identities of proteins that are responsible for sensing calcium changes and for transmitting the calcium signal to release machineries. Synaptotagmins are primarily expressed in brain and endocrine cells and exhibit diverse calcium binding properties. Synaptotagmin-1, -2 and -9 are calcium sensors for fast neurotransmitter release in respective brain regions, while synaptotagmin-7 is a positive regulator of calcium-dependent insulin release. Unlike the three neuronal calcium sensors, whose deletion abolished fast neurotransmitter release, synaptotagmin-7 deletion resulted in only partial loss of calcium-dependent insulin secretion, thus suggesting that other calcium-sensors must participate in the regulation of insulin secretion. Of the other synaptotagmin isoforms that are present in pancreatic islets, the neuronal calcium sensor synaptotagmin-9 is expressed at the highest level after synaptotagmin-7.
  
  
  RESULTS
  In this study we tested whether synaptotagmin-9 participates in the regulation of glucose-stimulated insulin release by using pancreas-specific synaptotagmin-9 knockout (p-S9X) mice. Deletion of synaptotagmin-9 in the pancreas resulted in no changes in glucose homeostasis or body weight. Glucose tolerance, and insulin secretion in vivo and from isolated islets were not affected in the p-S9X mice. Single-cell capacitance measurements showed no difference in insulin granule exocytosis between p-S9X and control mice.
  
  
  CONCLUSIONS
  Thus, synaptotagmin-9, although a major calcium sensor in the brain, is not involved in the regulation of glucose-stimulated insulin release from pancreatic β-cells.
authors.affiliation: Laboratory of Metabolic Medicine, Singapore Bioimaging Consortium, Agency for Science Technology and Research, Singapore. natalia_gustavsson@sbic.a-star.edu.sg
authors.forename: Natalia
authors.initials: N
authors.lastname: Gustavsson
authors.forename: Xiaorui
authors.initials: X
authors.lastname: Wang
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: Tingting
authors.initials: T
authors.lastname: Seah
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.forename: George K
authors.initials: GK
authors.lastname: Radda
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
authors.forename: Weiping
authors.initials: W
authors.lastname: Han
mesh_terms: D000818:Animals; D001835:Body Weight; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000502:physiology; D025802:Electric Capacitance; D005089:Exocytosis; D005260:Female; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D005951:Glucose Tolerance Test; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D009474:Neurons / Q000378:metabolism; D018408:Patch-Clamp Techniques; D050857:Synaptotagmins / Q000235:genetics / Q000378:metabolism*
chemical_list: D007328:Insulin; D050857:Synaptotagmins; D005947:Glucose; D002118:Calcium