Evidence of the receptor-mediated influence of melatonin on pancreatic glucagon secretion via the Gαq protein-coupled and PI3K signaling pathways
Article first published online: 4 JUN 2012
© 2012 John Wiley & Sons A/S
Journal of Pineal Research
Volume 53, Issue 4, pages 390–398, November 2012
How to Cite
Bähr, I., Mühlbauer, E., Albrecht, E. and Peschke, E. (2012), Evidence of the receptor-mediated influence of melatonin on pancreatic glucagon secretion via the Gαq protein-coupled and PI3K signaling pathways. Journal of Pineal Research, 53: 390–398. doi: 10.1111/j.1600-079X.2012.01009.x
- Issue published online: 18 OCT 2012
- Article first published online: 4 JUN 2012
- Accepted manuscript online: 9 MAY 2012 10:41AM EST
- Received March 29, 2012; Accepted May 4, 2012.
- glucose metabolism;
- MT1 and MT2 receptor;
- pancreatic α-cell;
- type 2 diabetes
Abstract: Melatonin has been shown to modulate glucose metabolism by influencing insulin secretion. Recent investigations have also indicated a regulatory function of melatonin on the pancreatic α-cells. The present in vitro and in vivo studies evaluated whether melatonin mediates its effects via melatonin receptors and which signaling cascade is involved. Incubation experiments using the glucagon-producing mouse pancreatic α-cell line αTC1 clone 9 (αTC1.9) as well as isolated pancreatic islets of rats and mice revealed that melatonin increases glucagon secretion. Preincubation of αTC1.9 cells with the melatonin receptor antagonists luzindole and 4P-PDOT abolished the glucagon-stimulatory effect of melatonin. In addition, glucagon secretion was lower in the pancreatic islets of melatonin receptor knockout mice than in the islets of the wild-type (WT) control animals. Investigations of melatonin receptor knockout mice revealed decreased plasma glucagon concentrations and elevated mRNA expression levels of the hepatic glucagon receptor when compared to WT mice. Furthermore, studies using pertussis toxin, as well as measurements of cAMP concentrations, ruled out the involvement of Gαi- and Gαs-coupled signaling cascades in mediating the glucagon increase induced by melatonin. In contrast, inhibition of phospholipase C in αTC1.9 cells prevented the melatonin-induced effect, indicating the physiological relevance of the Gαq-coupled pathway. Our data point to the involvement of the phosphatidylinositol 3-kinase signaling cascade in mediating melatonin effects in pancreatic α-cells. In conclusion, these findings provide evidence that the glucagon-stimulatory effect of melatonin in pancreatic α-cells is melatonin receptor mediated, thus supporting the concept of melatonin-modulated and diurnal glucagon release.