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

Jones, Helena LU ; Wierup, Nils LU ; Vikman, Jenny LU ; Manganiello, Vincent C; Degerman, Eva LU ; Eliasson, Lena LU and Stenson, Lena LU (2007) In Cellular Signalling 19(Feb 12). p.1505-1513
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
beta-cell, exocytosis, insulin, cAMP, phosphodiesterase 3B
in
Cellular Signalling
volume
19
issue
Feb 12
pages
1505 - 1513
publisher
Elsevier
external identifiers
  • wos:000247675500014
  • scopus:34249666189
ISSN
1873-3913
DOI
10.1016/j.cellsig.2007.01.030
language
English
LU publication?
yes
id
e4bc2c47-8e89-4ca9-b115-da4084f69405 (old id 166413)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17368848&dopt=Abstract
date added to LUP
2007-07-20 08:33:50
date last changed
2017-01-01 04:54:04
@article{e4bc2c47-8e89-4ca9-b115-da4084f69405,
  abstract     = {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.},
  author       = {Jones, Helena and Wierup, Nils and Vikman, Jenny and Manganiello, Vincent C and Degerman, Eva and Eliasson, Lena and Stenson, Lena},
  issn         = {1873-3913},
  keyword      = {beta-cell,exocytosis,insulin,cAMP,phosphodiesterase 3B},
  language     = {eng},
  number       = {Feb 12},
  pages        = {1505--1513},
  publisher    = {Elsevier},
  series       = {Cellular Signalling},
  title        = {beta-cell PDE3B regulates Ca(2+)-stimulated exocytosis of insulin.},
  url          = {http://dx.doi.org/10.1016/j.cellsig.2007.01.030},
  volume       = {19},
  year         = {2007},
}