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Endogenous and synthetic agonists of GPR119 differ in signalling pathways and their effects on insulin secretion in MIN6c4 insulinoma cells
- Source :
- British Journal of Pharmacology
- Publication Year :
- 2008
- Publisher :
- Nature Publishing Group, 2008.
-
Abstract
- Background and purpose: GPR119 is a G protein-coupled receptor that is preferentially expressed in islet cells and mediates insulin secretion. Oleoyl-lysophosphatidylcholine and oleoylethanolamide (OEA) act as endogenous ligands for this receptor, whereas PSN375963 and PSN632408 are two recently reported synthetic agonists. In this study, we explored mechanisms underlying GPR119-induced insulin secretion. In addition, we assessed the potential utility of the synthetic agonists as tools for exploring GPR119 biology. Experimental approach: We examined natural and synthetic GPR119 agonist activity at GPR119 in MIN6c4 and RINm5f insulinoma cells. We evaluated insulin secretion, intracellular calcium [Ca2+]i, ion channel involvement and levels of cAMP. Key results: We report that increases in insulin secretion induced by OEA were associated with increased cAMP and a potentiation of glucose-stimulated increases in [Ca2+]i. We also demonstrate that ATP-sensitive K+ and voltage-dependent calcium channels were required for GPR119-mediated increases in glucose-stimulated insulin secretion. In contrast to OEA, the synthetic GPR119 agonist PSN375963 and PSN632408 have divergent effects on insulin secretion, cAMP and intracellular calcium in MIN6c4 cells. Conclusions and implications: The endogenous ligand OEA signals through GPR119 in a manner similar to glucagon-like peptide-1 (GLP-1) and its receptor with respect to insulin secretion, [Ca2+]i and cAMP. In addition, PSN375963 and PSN632408 substantially differ from OEA and from one another. These studies suggest that the commercially available synthetic agonists, although they do activate GPR119, may also activate GPR119-independent pathways and are thus unsuitable as GPR119-specific pharmacological tools.
- Subjects :
- insulin secretion
Pyridones
Oleic Acids
oleoylethanolamide
Receptors, G-Protein-Coupled
Mice
Genitourinary, Renal and Endocrine Pharmacology
KATP Channels
cAMP
Cyclic AMP
Acids, Heterocyclic
Animals
Insulin
Cells, Cultured
calcium flux
Oxadiazoles
Lysophosphatidylcholines
Research Papers
Rats
Glucose
GPR119
agonists
Calcium
Insulinoma
Calcium Channels
GLP-1
Endocannabinoids
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 14765381 and 00071188
- Volume :
- 155
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- British Journal of Pharmacology
- Accession number :
- edsair.pmid..........f39f55f0cb35659c38210463b0d1a883