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

Olsen, HL; Hoy, M; Zhang, W; Bertorello, AM; Bokvist, K; Capito, K; Efanov, AM; Meister, B; Thams, P and Yang, SN, et al. (2003) In Proceedings of the National Academy of Sciences 100(9). p.5187-5192
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... (More)
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. (Less)
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keywords
insulin, Ca2+-dependent activator protein for secretion (CAPS), exocytosis, phosphoinositides
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Proceedings of the National Academy of Sciences
volume
100
issue
9
pages
5187 - 5192
publisher
National Acad Sciences
external identifiers
  • wos:000182612600042
  • pmid:12700357
  • scopus:0038303159
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1091-6490
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English
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@article{f5287eda-7d52-48dd-aff8-886afdf78ff3,
  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.},
  author       = {Olsen, HL and Hoy, M and Zhang, W and Bertorello, AM and Bokvist, K and Capito, K and Efanov, AM and Meister, B and Thams, P and Yang, SN and Rorsman, Patrik and Berggren, PO and Gromada, J},
  issn         = {1091-6490},
  keyword      = {insulin,Ca2+-dependent activator protein for secretion (CAPS),exocytosis,phosphoinositides},
  language     = {eng},
  number       = {9},
  pages        = {5187--5192},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Phosphatidylinositol 4-kinase serves as a metabolic sensor and regulates priming of secretory granules in pancreatic beta cells},
  url          = {http://dx.doi.org/},
  volume       = {100},
  year         = {2003},
}