Ong, W.K., Gribble, F.M., Reimann, F., Lynch, M.J., Houslay, M.D., Baillie, G.S. , Furman, B.L. and Pyne, N.J. (2009) The role of the PDE4D cAMP phosphodiesterase in the regulation of glucagon-like peptide-1 release. British Journal of Pharmacology, 157(4), pp. 633-644. (doi: 10.1111/j.1476-5381.2009.00194.x)
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Publisher's URL: http://dx.doi.org/10.1111/j.1476-5381.2009.00194.x
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•kg<sup>−1</sup> 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<sub>50</sub>∼1.2 nmol•L<sup>−1</sup>). 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.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Baillie, Professor George and Houslay, Professor Miles |
| Authors: | Ong, W.K., Gribble, F.M., Reimann, F., Lynch, M.J., Houslay, M.D., Baillie, G.S., Furman, B.L., and Pyne, N.J. |
| Subjects: | Q Science > QH Natural history > QH345 Biochemistry R Medicine > RM Therapeutics. Pharmacology |
| College/School: | College of Medical Veterinary and Life Sciences > School of Molecular Biosciences College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience |
| Journal Name: | British Journal of Pharmacology |
| Journal Abbr.: | BJP |
| Publisher: | John Wiley & Sons Ltd. |
| ISSN: | 0007-1188 |
| ISSN (Online): | 1476-5381 |
| Published Online: | 09 April 2009 |
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