Role of phosphodiesterase and adenylate cyclase isozymes in murine colonic glucagon-like peptide 1 secreting cells
| Autor: | Ronn S. Friedlander, Fiona M. Gribble, Gwen Tolhurst, Helen E. Parker, Dermot M.F. Cooper, Jessica Mace, Abdella M. Habib, Sebastian Wachten, Frank Reimann, Catherine E. Moss |
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| Rok vydání: | 2010 |
| Předmět: |
endocrine system
medicine.medical_specialty adenylate cyclase (AC) Colon Guanylin Enteroendocrine Cells Adenylate kinase 030209 endocrinology & metabolism Enteroendocrine cell Mice Transgenic Biology guanylin Isozyme Cyclase 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Internal medicine medicine Cyclic AMP Animals Secretion Cyclic adenosine monophosphate Intestinal Mucosa Cells Cultured cyclic adenosine monophosphate 030304 developmental biology Pharmacology 0303 health sciences Phosphoric Diester Hydrolases digestive oral and skin physiology Phosphodiesterase Research Papers glucagon-like peptide 1 Isoenzymes Endocrinology chemistry phosphodiesterase hormones hormone substitutes and hormone antagonists Adenylyl Cyclases |
| Zdroj: | British Journal of Pharmacology |
| ISSN: | 1476-5381 |
| Popis: | BACKGROUND AND PURPOSE Glucagon-like peptide-1 (GLP-1) is secreted from enteroendocrine L-cells after food intake. Increasing GLP-1 signalling either through inhibition of the GLP-1 degrading enzyme dipeptidyl-peptidase IV or injection of GLP-1-mimetics has recently been successfully introduced for the treatment of type 2 diabetes. Boosting secretion from the L-cell has so far not been exploited, due to our incomplete understanding of L-cell physiology. Elevation of cyclic adenosine monophosphate (cAMP) has been shown to be a strong stimulus for GLP-1 secretion and here we investigate the activities of adenylate cyclase (AC) and phosphodiesterase (PDE) isozymes likely to shape cAMP responses in L-cells. EXPERIMENTAL APPROACH Expression of AC and PDE isoforms was quantified by RT-PCR. Single cell responses to stimulation or inhibition of AC and PDE isoforms were monitored with real-time cAMP probes. GLP-1 secretion was assessed by elisa. KEY RESULTS Quantitative PCR identified expression of protein kinase C- and Ca2+-activated ACs, corresponding with phorbolester and cytosolic Ca2+-stimulated cAMP elevation. Inhibition of PDE2, 3 and 4 were found to stimulate GLP-1 secretion from murine L-cells in primary culture. This corresponded with cAMP elevations monitored with a plasma membrane targeted cAMP probe. Inhibition of PDE3 but not PDE2 was further shown to prevent GLP-1 secretion in response to guanylin, a peptide secreted into the gut lumen, which had not previously been implicated in L-cell secretion. CONCLUSIONS AND IMPLICATIONS Our results reveal several mechanisms shaping cAMP responses in GLP-1 secreting cells, with some of the molecular components specifically expressed in L-cells when compared with their epithelial neighbours, thus opening new strategies for targeting these cells therapeutically. |
| Databáze: | OpenAIRE |
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