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

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 output: Contribution to journalArticlepeer-review

    81 Citations (SciVal)

    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.
    Original languageEnglish
    Pages (from-to)5187-5192
    JournalProceedings of the National Academy of Sciences
    Volume100
    Issue number9
    DOIs
    Publication statusPublished - 2003

    Subject classification (UKÄ)

    • Endocrinology and Diabetes

    Keywords

    • insulin
    • Ca2+-dependent activator protein for secretion (CAPS)
    • exocytosis
    • phosphoinositides

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