The calcium/calmodulin-dependent phosphodiesterase PDE1C down-regulates glucose-induced insulin secretion

Ping Han, John Werber, Manju Surana, Norman Fleischer, Tamar Michaeli

Research output: Contribution to journalArticle

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Abstract

To understand the role cAMP phosphodiesterases (PDEs) play in the regulation of insulin secretion, we analyzed cyclic nucleotide PDEs of a pancreatic β-cell line and used family and isozyme-specific PDE inhibitors to identify the PDEs that counteract glucose-stimulated insulin secretion. We demonstrate the presence of soluble PDE1C, PDE4A and 4D, a cGMP-specific PDE, and of particulate PDE3, activities in βTC3 insulinoma cells. Selective inhibition of PDE1C, but not of PDE4, augmented glucose-stimulated insulin secretion in a dose-dependent fashion thus demonstrating that PDE1C is the major PDE counteracting glucose-dependent insulin secretion from βTC3 cells. In pancreatic islets, inhibition of both PDE1C and PDE3 augmented glucose- dependent insulin secretion. The PDE1C of βTC3 cells is a novel isozyme possessing a K(m) of 0.47 μM for cAMP and 0.25 μM for cGMP. The PDE1C isozyme of βTC3 cells is sensitive to 8-methoxymethyl isobutylmethylxanthine and zaprinast (IC50 = 7.5 and 4.5 μM, respectively) and resistant to vinpocetine (IC50 > 100 μM). Increased responsiveness of PDE1C activity to calcium/calmodulin is evident upon exposure of cells to glucose. Enhanced cAMP degradation by PDE1C, due to increases in its responsiveness to calcium/calmodulin and in intracellular calcium, constitutes a glucose- dependent feedback mechanism for the control of insulin secretion.

Original languageEnglish (US)
Pages (from-to)22337-22344
Number of pages8
JournalJournal of Biological Chemistry
Volume274
Issue number32
DOIs
StatePublished - Aug 6 1999

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Type 1 Cyclic Nucleotide Phosphodiesterases
Phosphoric Diester Hydrolases
Down-Regulation
Insulin
Glucose
Isoenzymes
vinpocetine
Calmodulin
Calcium
Inhibitory Concentration 50
Insulinoma
Phosphodiesterase Inhibitors
Cyclic Nucleotides
Islets of Langerhans
Cells
Feedback
Cell Line
Degradation

ASJC Scopus subject areas

  • Biochemistry

Cite this

The calcium/calmodulin-dependent phosphodiesterase PDE1C down-regulates glucose-induced insulin secretion. / Han, Ping; Werber, John; Surana, Manju; Fleischer, Norman; Michaeli, Tamar.

In: Journal of Biological Chemistry, Vol. 274, No. 32, 06.08.1999, p. 22337-22344.

Research output: Contribution to journalArticle

Han, Ping ; Werber, John ; Surana, Manju ; Fleischer, Norman ; Michaeli, Tamar. / The calcium/calmodulin-dependent phosphodiesterase PDE1C down-regulates glucose-induced insulin secretion. In: Journal of Biological Chemistry. 1999 ; Vol. 274, No. 32. pp. 22337-22344.
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