E. M. and E. A. equally contributed to the manuscript.
Melatonin inhibits insulin secretion in rat insulinoma β-cells (INS-1) heterologously expressing the human melatonin receptor isoform MT2
Article first published online: 17 MAY 2011
© 2011 John Wiley & Sons A/S
Journal of Pineal Research
Volume 51, Issue 3, pages 361–372, October 2011
How to Cite
Mühlbauer, E., Albrecht, E., Hofmann, K., Bazwinsky-Wutschke, I. and Peschke, E. (2011), Melatonin inhibits insulin secretion in rat insulinoma β-cells (INS-1) heterologously expressing the human melatonin receptor isoform MT2. Journal of Pineal Research, 51: 361–372. doi: 10.1111/j.1600-079X.2011.00898.x
- Issue published online: 20 SEP 2011
- Article first published online: 17 MAY 2011
- Accepted manuscript online: 21 APR 2011 11:45AM EST
- Received March 7, 2011; Accepted April 15, 2011.
- insulin secretion;
- melatonin receptor MT2;
- rat insulinoma β-cell line (INS-1);
- second messenger;
- signal transduction
Abstract: Melatonin exerts some of its effects via G-protein-coupled membrane receptors. Two membrane receptor isoforms, MT1 and MT2, have been described. The MT1 receptor is known to inhibit second messenger cyclic adenosine monophosphate (cAMP) signaling through receptor-coupling to inhibitory G-proteins (Gi). Much less is known about the MT2 receptor, but it has also been implicated in signaling via Gi-proteins. In rat pancreatic β-cells, it has recently been reported that the MT2 receptor plays an inhibitory role in the cyclic guanosine monophosphate (cGMP) pathway. This study addresses the signaling features of the constitutively expressed human recombinant MT2 receptor (hMT2) and its impact on insulin secretion, using a rat insulinoma β-cell line (INS-1). On the basis of a specific radioimmunoassay, insulin secretion was found to be more strongly reduced in the clones expressing hMT2 than in INS-1 controls, when incubated with 1 or 100 nm melatonin. Similarly, cAMP and cGMP levels, measured by specific enzyme-linked immunosorbent assays (ELISAs), were reduced to a greater extent in hMT2 clones after melatonin treatment. In hMT2-expressing cells, the inhibitory effect of melatonin on insulin secretion was blocked by pretreatment with pertussis toxin, demonstrating the coupling of the hMT2 to Gi-proteins. These results indicate that functional hMT2 expression leads to the inhibition of cyclic nucleotide signaling and a reduction in insulin release. Because genetic variants of the hMT2 receptor are considered to be risk factors in the development of type 2 diabetes, our results are potentially significant in explaining and preventing the pathogenesis of this disease.