title: Requirement of inositol pyrophosphates for full exocytotic capacity in pancreatic beta cells.
abstract: Inositol pyrophosphates are recognized components of cellular processes that regulate vesicle trafficking, telomere length, and apoptosis. We observed that pancreatic beta cells maintain high basal concentrations of the pyrophosphate diphosphoinositol pentakisphosphate (InsP7 or IP7). Inositol hexakisphosphate kinases (IP6Ks) that can generate IP7 were overexpressed. This overexpression stimulated exocytosis of insulin-containing granules from the readily releasable pool. Exogenously applied IP7 dose-dependently enhanced exocytosis at physiological concentrations. We determined that IP6K1 and IP6K2 were present in beta cells. RNA silencing of IP6K1, but not IP6K2, inhibited exocytosis, which suggests that IP6K1 is the critical endogenous kinase. Maintenance of high concentrations of IP7 in the pancreatic beta cell may enhance the immediate exocytotic capacity and consequently allow rapid adjustment of insulin secretion in response to increased demand.
authors.affiliation: Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76, Stockholm, Sweden.
authors.forename: Christopher
authors.initials: C
authors.lastname: Illies
authors.forename: Jesper
authors.initials: J
authors.lastname: Gromada
authors.forename: Roberta
authors.initials: R
authors.lastname: Fiume
authors.forename: Barbara
authors.initials: B
authors.lastname: Leibiger
authors.forename: Jia
authors.initials: J
authors.lastname: Yu
authors.forename: Kirstine
authors.initials: K
authors.lastname: Juhl
authors.forename: Shao-Nian
authors.initials: SN
authors.lastname: Yang
authors.forename: Deb K
authors.initials: DK
authors.lastname: Barma
authors.forename: John R
authors.initials: JR
authors.lastname: Falck
authors.forename: Adolfo
authors.initials: A
authors.lastname: Saiardi
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Barker
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
mesh_terms: D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D025802:Electric Capacitance; D005089:Exocytosis; D007295:Inositol Phosphates / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D018408:Patch-Clamp Techniques; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000235:genetics / Q000378:metabolism; D010833:Phytic Acid / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D022142:Secretory Vesicles / Q000378:metabolism*; D014162:Transfection
chemical_list: C485444:Ihpk1 protein, mouse; D007295:Inositol Phosphates; D007328:Insulin; C079849:1-diphosphoinositol pentakisphosphate; D010833:Phytic Acid; D017856:Phosphotransferases (Phosphate Group Acceptor); C099438:inositol hexakisphosphate kinase