Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 318 (5854): 1299-1302

Copyright © 2007 by the American Association for the Advancement of Science

Requirement of Inositol Pyrophosphates for Full Exocytotic Capacity in Pancreatic β Cells

Christopher Illies,1 Jesper Gromada,2 Roberta Fiume,1 Barbara Leibiger,1 Jia Yu,1 Kirstine Juhl,3 Shao-Nian Yang,1 Deb K. Barma,4 John R. Falck,4 Adolfo Saiardi,5 Christopher J. Barker,1* Per-Olof Berggren1

Abstract: Inositol pyrophosphates are recognized components of cellular processes that regulate vesicle trafficking, telomere length, and apoptosis. We observed that pancreatic β cells maintain high basal concentrations of the pyrophosphate diphosphoinositol pentakisphosphate (InsP7 or IP7). Inositol hexakisphosphate kinases (IP6Ks) that can generate IP7 were overexpressed. This overexpression stimulated exocytosis of insulin-containing granules from the readily releasable pool. Exogenously applied IP7 dose-dependently enhanced exocytosis at physiological concentrations. We determined that IP6K1 and IP6K2 were present in β cells. RNA silencing of IP6K1, but not IP6K2, inhibited exocytosis, which suggests that IP6K1 is the critical endogenous kinase. Maintenance of high concentrations of IP7 in the pancreatic β cell may enhance the immediate exocytotic capacity and consequently allow rapid adjustment of insulin secretion in response to increased demand.

1 The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76, Stockholm, Sweden.
2 Diabetes and Metabolism Disease Area, Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA.
3 Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
4 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
5 U.K. Medical Research Council (MRC) Cell Biology Unit and Laboratory for Molecular Cell Biology, Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, UK.

* To whom correspondence should be addressed. E-mail: chris.barker{at}ki.se


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Inositol pyrophosphates regulate JMJD2C-dependent histone demethylation.
A. Burton, C. Azevedo, C. Andreassi, A. Riccio, and A. Saiardi (2013)
PNAS 110, 18970-18975
   Abstract »    Full Text »    PDF »
Cigarette smoke (CS) and nicotine delay neutrophil spontaneous death via suppressing production of diphosphoinositol pentakisphosphate.
Y. Xu, H. Li, B. Bajrami, H. Kwak, S. Cao, P. Liu, J. Zhou, Y. Zhou, H. Zhu, K. Ye, et al. (2013)
PNAS 110, 7726-7731
   Abstract »    Full Text »    PDF »
New Horizons in Cellular Regulation by Inositol Polyphosphates: Insights from the Pancreatic {beta}-Cell.
C. J. Barker and P.-O. Berggren (2013)
Pharmacol. Rev. 65, 641-669
   Abstract »    Full Text »    PDF »
Phospholipid Scramblase-1-Induced Lipid Reorganization Regulates Compensatory Endocytosis in Neuroendocrine Cells.
S. Ory, M. Ceridono, F. Momboisse, S. Houy, S. Chasserot-Golaz, D. Heintz, V. Calco, A.-M. Haeberle, F. A. Espinoza, P. J. Sims, et al. (2013)
J. Neurosci. 33, 3545-3556
   Abstract »    Full Text »    PDF »
Inositol Pyrophosphate Synthesis by Inositol Hexakisphosphate Kinase 1 Is Required for Homologous Recombination Repair.
R. S. Jadav, M. V. L. Chanduri, S. Sengupta, and R. Bhandari (2013)
J. Biol. Chem. 288, 3312-3321
   Abstract »    Full Text »    PDF »
Influence of Inositol Pyrophosphates on Cellular Energy Dynamics.
Z. Szijgyarto, A. Garedew, C. Azevedo, and A. Saiardi (2011)
Science 334, 802-805
   Abstract »    Full Text »    PDF »
Inositol Pyrophosphates as Mammalian Cell Signals.
A. Chakraborty, S. Kim, and S. H. Snyder (2011)
Science Signaling 4, re1
   Abstract »    Full Text »    PDF »
Inositol Hexakisphosphate Kinases Induce Cell Death in Huntington Disease.
E. Nagata, A. Saiardi, H. Tsukamoto, Y. Okada, Y. Itoh, T. Satoh, J. Itoh, R. L. Margolis, S. Takizawa, A. Sawa, et al. (2011)
J. Biol. Chem. 286, 26680-26686
   Abstract »    Full Text »    PDF »
p53-mediated apoptosis requires inositol hexakisphosphate kinase-2.
M. A. Koldobskiy, A. Chakraborty, J. K. Werner Jr., A. M. Snowman, K. R. Juluri, M. S. Vandiver, S. Kim, S. Heletz, and S. H. Snyder (2010)
PNAS 107, 20947-20951
   Abstract »    Full Text »    PDF »
Inositol hexakisphosphate kinase-2 acts as an effector of the vertebrate Hedgehog pathway.
B. Sarmah and S. R. Wente (2010)
PNAS 107, 19921-19926
   Abstract »    Full Text »    PDF »
Inositol pyrophosphate mediated pyrophosphorylation of AP3B1 regulates HIV-1 Gag release.
C. Azevedo, A. Burton, E. Ruiz-Mateos, M. Marsh, and A. Saiardi (2009)
PNAS 106, 21161-21166
   Abstract »    Full Text »    PDF »
The Arabidopsis ATP-binding Cassette Protein AtMRP5/AtABCC5 Is a High Affinity Inositol Hexakisphosphate Transporter Involved in Guard Cell Signaling and Phytate Storage.
R. Nagy, H. Grob, B. Weder, P. Green, M. Klein, A. Frelet-Barrand, J. K. Schjoerring, C. Brearley, and E. Martinoia (2009)
J. Biol. Chem. 284, 33614-33622
   Abstract »    Full Text »    PDF »
Diphosphoinositol Polyphosphates: Metabolic Messengers?.
S. B. Shears (2009)
Mol. Pharmacol. 76, 236-252
   Abstract »    Full Text »    PDF »
CAPS Activity in Priming Vesicle Exocytosis Requires CK2 Phosphorylation.
M. Nojiri, K. M. Loyet, V. A. Klenchin, G. Kabachinski, and T. F. J. Martin (2009)
J. Biol. Chem. 284, 18707-18714
   Abstract »    Full Text »    PDF »
Characterization of a Selective Inhibitor of Inositol Hexakisphosphate Kinases: USE IN DEFINING BIOLOGICAL ROLES AND METABOLIC RELATIONSHIPS OF INOSITOL PYROPHOSPHATES.
U. Padmanabhan, D. E. Dollins, P. C. Fridy, J. D. York, and C. P. Downes (2009)
J. Biol. Chem. 284, 10571-10582
   Abstract »    Full Text »    PDF »
Dual Functions for the Schizosaccharomyces pombe Inositol Kinase Ipk1 in Nuclear mRNA Export and Polarized Cell Growth.
B. Sarmah and S. R. Wente (2009)
Eukaryot. Cell 8, 134-146
   Abstract »    Full Text »    PDF »
The Nucleolus Exhibits an Osmotically Regulated Gatekeeping Activity That Controls the Spatial Dynamics and Functions of Nucleolin.
L. Yang, J. M. Reece, J. Cho, C. D. Bortner, and S. B. Shears (2008)
J. Biol. Chem. 283, 11823-11831
   Abstract »    Full Text »    PDF »
Highlights From The Literature.
(2008)
Physiology 23, 61-63
   Full Text »    PDF »
Gene deletion of inositol hexakisphosphate kinase 1 reveals inositol pyrophosphate regulation of insulin secretion, growth, and spermiogenesis.
R. Bhandari, K. R. Juluri, A. C. Resnick, and S. H. Snyder (2008)
PNAS 105, 2349-2353
   Abstract »    Full Text »    PDF »
IP7 Debut in Insulin Release.
S. Nagamatsu and M. Ohara-Imaizumi (2007)
Science 318, 1249-1250
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882