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

Ong, W.K. and Gribble, F.M. and Reimann, F. and Lynch, M.J. and Houslay, M.D. and Baillie, G.S. and 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. ISSN 1476-5381

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Abstract

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. 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. Rolipram (1.5 mg.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 (EC50 similar to 1.2 nmol.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. PDE4D may play an important role in regulating intracellular cAMP linked to the regulation of GLP-1 release.