title: Phosphatidylinositol 4-kinase serves as a metabolic sensor and regulates priming of secretory granules in pancreatic beta cells.
abstract: Insulin secretion is controlled by the beta cell's metabolic state, and the ability of the secretory granules to undergo exocytosis increases during glucose stimulation in a membrane potential-independent fashion. Here, we demonstrate that exocytosis of insulin-containing secretory granules depends on phosphatidylinositol 4-kinase (PI 4-kinase) activity and that inhibition of this enzyme suppresses glucose-stimulated insulin secretion. Intracellular application of phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate [PI(4,5)P(2)] stimulated exocytosis by promoting the priming of secretory granules for release and increasing the number of granules residing in a readily releasable pool. Reducing the cytoplasmic ADP concentration in a way mimicking the effects of glucose stimulation activated PI 4-kinase and increased exocytosis whereas changes of the ATP concentration in the physiological range had little effect. The PI(4,5)P(2)-binding protein Ca(2+)-dependent activator protein for secretion (CAPS) is present in beta cells, and neutralization of the protein abolished both Ca(2+)- and PI(4,5)P(2)-induced exocytosis. We conclude that ADP-induced changes in PI 4-kinase activity, via generation of PI(4,5)P(2), represents a metabolic sensor in the beta cell by virtue of its capacity to regulate the release competence of the secretory granules.
authors.affiliation: Islet Cell Physiology, Novo Nordisk AS, Novo Alle, DK-2880 Bagsvaerd, Denmark.
authors.forename: Hervør L
authors.initials: HL
authors.lastname: Olsen
authors.forename: Marianne
authors.initials: M
authors.lastname: Hoy
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Alejandro M
authors.initials: AM
authors.lastname: Bertorello
authors.forename: Krister
authors.initials: K
authors.lastname: Bokvist
authors.forename: Kirsten
authors.initials: K
authors.lastname: Capito
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Efanov
authors.forename: Björn
authors.initials: B
authors.lastname: Meister
authors.forename: Peter
authors.initials: P
authors.lastname: Thams
authors.forename: Shao-Nian
authors.initials: SN
authors.lastname: Yang
authors.forename: Patrik
authors.initials: P
authors.lastname: Rorsman
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
authors.forename: Jesper
authors.initials: J
authors.lastname: Gromada
mesh_terms: D019870:1-Phosphatidylinositol 4-Kinase / Q000378:metabolism*; D000818:Animals; D015374:Biosensing Techniques; D005089:Exocytosis; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000201:enzymology / Q000378:metabolism*; D051379:Mice
chemical_list: D007328:Insulin; D019870:1-Phosphatidylinositol 4-Kinase