Phosphatidylinositol 4-kinase serves as a metabolic sensor and regulates priming of secretory granules in pancreatic beta cells

Research output: Contribution to journalArticle

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 phosphaticlylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate [Pl(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 Ca2+-dependent activator protein for secretion (CAPS) is present in beta cells, and neutralization of the protein abolished both Ca2+- and PI(4,5)P-2-induced exocytosis. We conclude that ADP-induced changes in PI 4-kinase activity, via generation of Pl(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.

Details

Authors
  • HL Olsen
  • M Hoy
  • W Zhang
  • AM Bertorello
  • K Bokvist
  • K Capito
  • AM Efanov
  • B Meister
  • P Thams
  • SN Yang
  • Patrik Rorsman
  • PO Berggren
  • J Gromada
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes

Keywords

  • insulin, Ca2+-dependent activator protein for secretion (CAPS), exocytosis, phosphoinositides
Original languageEnglish
Pages (from-to)5187-5192
JournalProceedings of the National Academy of Sciences
Volume100
Issue number9
Publication statusPublished - 2003
Publication categoryResearch
Peer-reviewedYes