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Br J Pharmacol. 2009 Jun;157(4):633-44. doi: 10.1111/j.1476-5381.2009.00194.x. Epub 2009 Apr 9.

The role of the PDE4D cAMP phosphodiesterase in the regulation of glucagon-like peptide-1 release.

Author information

1
Strathclyde Institute of Pharmacy, Cell Biology Group, University of Strathclyde, Glasgow, UK.

Abstract

BACKGROUND AND PURPOSE:

Increases in intracellular cyclic AMP (cAMP) augment the release/secretion of glucagon-like peptide-1 (GLP-1). As cAMP is hydrolysed by cAMP phosphodiesterases (PDEs), we determined the role of PDEs and particularly PDE4 in regulating GLP-1 release.

EXPERIMENTAL APPROACH:

GLP-1 release, PDE expression and activity were investigated using rats and GLUTag cells, a GLP-1-releasing cell line. The effects of rolipram, a selective PDE4 inhibitor both in vivo and in vitro and stably overexpressed catalytically inactive PDE4D5 (D556A-PDE4D5) mutant in vitro on GLP-1 release were investigated.

KEY RESULTS:

Rolipram (1.5 mg x kg(-1) i.v.) increased plasma GLP-1 concentrations approximately twofold above controls in anaesthetized rats and enhanced glucose-induced GLP-1 release in GLUTag cells (EC(50) approximately 1.2 nmol x L(-1)). PDE4D mRNA transcript and protein were detected in GLUTag cells using RT-PCR with gene-specific primers and Western blotting with a specific PDE4D antibody respectively. Moreover, significant PDE activity was inhibited by rolipram in GLUTag cells. A GLUTag cell clone (C1) stably overexpressing the D556A-PDE4D5 mutant, exhibited elevated intracellular cAMP levels and increased basal and glucose-induced GLP-1 release compared with vector-transfected control cells. A role for intracellular cAMP/PKA in enhancing GLP-1 release in response to overexpression of D556A-PDE4D5 mutant was demonstrated by the finding that the PKA inhibitor H89 reduced both basal and glucose-induced GLP-1 release by 37% and 39%, respectively, from C1 GLUTag cells.

CONCLUSIONS AND IMPLICATIONS:

PDE4D may play an important role in regulating intracellular cAMP linked to the regulation of GLP-1 release.

PMID:
19371330
PMCID:
PMC2707975
DOI:
10.1111/j.1476-5381.2009.00194.x
[Indexed for MEDLINE]
Free PMC Article

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