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

Hervør L. Olsen, Marianne Høy, Wei Zhang, Alejandro M. Bertorello, Krister Bokvist, Kirsten Capito, Alexander M. Efanov, Björn Meister, Peter Thams, Shao Nian Yang, Patrik Rorsman, Per Olof Berggren, Jesper Gromada

Research output: Contribution to journalArticle

78 Scopus citations

Abstract

Insulin secretion is controlled by the β 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 insulincontaining 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)P2] 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)P2-binding protein Ca2+-dependent activator protein for secretion (CAPS) is present in β cells, and neutralization of the protein abolished both Ca2+- and PI(4,5)P2-induced exocytosis. We conclude that ADPinduced changes in PI 4-kinase activity, via generation of PI(4,5)P2, represents a metabolic sensor in the β cell by virtue of its capacity to regulate the release competence of the secretory granules.

Original languageEnglish (US)
Pages (from-to)5187-5192
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number9
DOIs
StatePublished - Apr 29 2003

Keywords

  • Ca-dependent activator protein for secretion (CAPS)
  • Exocytosis
  • Insulin
  • Phosphoinositides

ASJC Scopus subject areas

  • Genetics
  • General

Fingerprint Dive into the research topics of 'Phosphatidylinositol 4-kinase serves as a metabolic sensor and regulates priming of secretory granules in pancreatic β cells'. Together they form a unique fingerprint.

  • Cite this

    Olsen, H. L., Høy, M., Zhang, W., Bertorello, A. M., Bokvist, K., Capito, K., Efanov, A. M., Meister, B., Thams, P., Yang, S. N., Rorsman, P., Berggren, P. O., & Gromada, J. (2003). Phosphatidylinositol 4-kinase serves as a metabolic sensor and regulates priming of secretory granules in pancreatic β cells. Proceedings of the National Academy of Sciences of the United States of America, 100(9), 5187-5192. https://doi.org/10.1073/pnas.0931282100