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beta-cell PDE3B regulates Ca(2+)-stimulated exocytosis of insulin.

Author:
  • Helena Jones
  • Nils Wierup
  • Jenny Vikman
  • Vincent C Manganiello
  • Eva Degerman
  • Lena Eliasson
  • Lena Stenson
Publishing year: 2007
Language: English
Pages: 1505-1513
Publication/Series: Cellular Signalling
Volume: 19
Issue: Feb 12
Document type: Journal article
Publisher: Elsevier

Abstract english

CAMP signaling is important for the regulation of insulin secretion in pancreatic beta-cells. The level of intracellular cAMP is controlled through its production by adenylyl cyclases and its breakdown by cyclic nucleotide phosphodiesterases (PDEs). We have previously shown that PDE3B is involved in the regulation of nutrient-stimulated insulin secretion. Here, aiming at getting deeper functional insights, we have examined the role of PDE3B in the two phases of insulin secretion as well as its localization in the beta-cell. Depolarization-induced insulin secretion was assessed and in models where PDE3B was overexpressed [islets from transgenic RIP-PDE3B/7 mice and adenovirally (AdPDE3B) infected INS-I (832/13) cells], the first phase of insulin secretion, occurring in response to stimulation with high K+ for 5 min, was significantly reduced (similar to 25% compared to controls). In contrast, in islets from PDE3B(-/-) mice the response to high K+ was increased. Further, stimulation of isolated beta-cells from RIP-PDE3B/7 islets, using successive trains of voltage-clamped depolarizations, resulted in reduced Ca2+-triggered first phase exocytotic response as well as reduced granule mobilization-dependent second phase, compared to wild-type beta-cells. Using sub-cellular fractionation, confocal microscopy and transmission electron microscopy of isolated mouse islets and INS-1 (832/13) cells, we show that endogenous and overexpressed PDE3B is localized to insulin granules and plasma membrane. We conclude that PDE3B, through hydrolysis of cAMP in pools regulated by Ca2+, plays a regulatory role in depolarization-induced insulin secretion and that the enzyme is associated with the exocytotic machinery in beta-cells. (c) 2007 Elsevier Inc. All rights reserved.

Keywords

  • Microbiology
  • beta-cell
  • exocytosis
  • insulin
  • cAMP
  • phosphodiesterase 3B

Other

Published
  • Molecular Endocrinology
  • Insulin Signal Transduction
  • Neuroendocrine Cell Biology
  • Islet cell exocytosis
  • ISSN: 1873-3913
Eva Degerman
E-mail: eva.degerman [at] med.lu.se

Professor

Insulin Signal Transduction

+46 46 222 85 83

+46 70 885 83 62

BMC C1121b

66

Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00