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Important role of phosphodiesterase 3B for the stimulatory action of cAMP on pancreatic beta -cell exocytosis and release of insulin.

Härndahl, Linda LU ; Jing, Xingjun LU ; Ivarsson, Rosita LU ; Degerman, Eva LU ; Ahrén, Bo LU ; Manganiello, Vincent C.; Renström, Erik LU and Stenson Holst, Lena (2002) In Journal of Biological Chemistry 277(40). p.37446-37455
Abstract
Cyclic AMP potentiates glucose-stimulated insulin release and mediates the stimulatory effects of hormones such as glucagon-like peptide 1 (GLP-1) on pancreatic b-cells. By inhibition of cAMP-degrading phosphodiesterase (PDE) and, in particular, selective inhibition of PDE3 activity, stimulatory effects on insulin secretion have been observed. Molecular and functional information on b-cell PDE3 is, however, scarce. To provide such information, we have studied the specific effects of the PDE3B isoform by adenovirus-mediated overexpression. In rat islets and rat insulinoma cells, approximate 10-fold overexpression of PDE3B was accompanied by a 6-8-fold increase in membrane-associated PDE3B activity. The cAMP concentration was significantly... (More)
Cyclic AMP potentiates glucose-stimulated insulin release and mediates the stimulatory effects of hormones such as glucagon-like peptide 1 (GLP-1) on pancreatic b-cells. By inhibition of cAMP-degrading phosphodiesterase (PDE) and, in particular, selective inhibition of PDE3 activity, stimulatory effects on insulin secretion have been observed. Molecular and functional information on b-cell PDE3 is, however, scarce. To provide such information, we have studied the specific effects of the PDE3B isoform by adenovirus-mediated overexpression. In rat islets and rat insulinoma cells, approximate 10-fold overexpression of PDE3B was accompanied by a 6-8-fold increase in membrane-associated PDE3B activity. The cAMP concentration was significantly lowered in transduced cells (INS-1(832/13), and insulin secretion in response to stimulation with high glucose (11.1 mM) was reduced by 40% (islets) and 50% (INS-1). Further, the ability of GLP-1 (100 nM) to augment glucose-stimulated insulin secretion was inhibited by approximately 30% (islets) and 70% (INS-1). Accordingly, when stimulating with cAMP, a substantial decrease (65%) in exocytotic capacity was demonstrated in patch-clamped single b-cells. In untransduced insulinoma cells, application of the PDE3-selective inhibitor OPC3911 (10 mM) was shown to increase glucose-stimulated insulin release as well as cAMP-enhanced exocytosis. The findings suggest a significant role of PDE3B as an important regulator of insulin secretory processes. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
277
issue
40
pages
37446 - 37455
publisher
ASBMB
external identifiers
  • wos:000178447100069
  • scopus:0037020258
ISSN
1083-351X
DOI
10.1074/jbc.M205401200
language
English
LU publication?
yes
id
e69a0cd3-75ee-46bb-b656-b2b9a9a0adde (old id 109842)
alternative location
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=12169692&ordinalpos=6&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
date added to LUP
2007-06-29 09:29:40
date last changed
2017-09-03 03:45:38
@article{e69a0cd3-75ee-46bb-b656-b2b9a9a0adde,
  abstract     = {Cyclic AMP potentiates glucose-stimulated insulin release and mediates the stimulatory effects of hormones such as glucagon-like peptide 1 (GLP-1) on pancreatic b-cells. By inhibition of cAMP-degrading phosphodiesterase (PDE) and, in particular, selective inhibition of PDE3 activity, stimulatory effects on insulin secretion have been observed. Molecular and functional information on b-cell PDE3 is, however, scarce. To provide such information, we have studied the specific effects of the PDE3B isoform by adenovirus-mediated overexpression. In rat islets and rat insulinoma cells, approximate 10-fold overexpression of PDE3B was accompanied by a 6-8-fold increase in membrane-associated PDE3B activity. The cAMP concentration was significantly lowered in transduced cells (INS-1(832/13), and insulin secretion in response to stimulation with high glucose (11.1 mM) was reduced by 40% (islets) and 50% (INS-1). Further, the ability of GLP-1 (100 nM) to augment glucose-stimulated insulin secretion was inhibited by approximately 30% (islets) and 70% (INS-1). Accordingly, when stimulating with cAMP, a substantial decrease (65%) in exocytotic capacity was demonstrated in patch-clamped single b-cells. In untransduced insulinoma cells, application of the PDE3-selective inhibitor OPC3911 (10 mM) was shown to increase glucose-stimulated insulin release as well as cAMP-enhanced exocytosis. The findings suggest a significant role of PDE3B as an important regulator of insulin secretory processes.},
  author       = {Härndahl, Linda and Jing, Xingjun and Ivarsson, Rosita and Degerman, Eva and Ahrén, Bo and Manganiello, Vincent C. and Renström, Erik and Stenson Holst, Lena},
  issn         = {1083-351X},
  language     = {eng},
  number       = {40},
  pages        = {37446--37455},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Important role of phosphodiesterase 3B for the stimulatory action of cAMP on pancreatic beta -cell exocytosis and release of insulin.},
  url          = {http://dx.doi.org/10.1074/jbc.M205401200},
  volume       = {277},
  year         = {2002},
}