Modulation of the cGMP signaling pathway by melatonin in pancreatic β‐cells

Abstract

Melatonin influences the second messenger cyclic guanosine 3',5'-monophosphate (cGMP) signaling pathway in pancreatic beta-cells via a receptor-mediated mechanism. In the present study, it was determined how the regulation of cGMP concentrations by melatonin proceeds. The results provide evidence that melatonin acts via the soluble guanylate cyclase (sGC), as molecular investigations demonstrated that long-term incubation with melatonin significantly reduced the expression levels of the sGC mRNA in rat insulinoma beta-cells (INS1) cells, whereas mRNA expression of membrane guanylate cyclases was unaffected. Incubation with melatonin abolished the S-nitrosoacetyl penicillamine-induced increase of cGMP concentrations in INS1 cells. In addition, the cGMP-inhibitory effect of melatonin was reversed by preincubation with the sGC inhibitors 1H-(1,2,4)oxadiazolo(4,3-alpha)quinoxalin-1-one and 4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one. Nitric oxide (NO) production was not influenced after 1 hr of melatonin application, but was influenced after a 4 hr incubation period. Preincubation of INS1 cells with the NO synthase inhibitor N(G)-monomethyl-l-arginine did not abolish the cGMP-inhibitory effect of melatonin. Transcripts of cyclic nucleotide-gated (CNG) channels were significantly reduced after melatonin treatment in a dose-dependent manner, indicating the involvement of these channels in mediating the melatonin effect in INS1 cells. The results of this study demonstrate that melatonin mediates its inhibitory effect on cGMP concentrations in pancreatic beta-cells by inhibiting the sGC, but does not influence NO concentration or NO synthase activity in short-term incubation experiments. In addition, it was demonstrated that melatonin is involved in modulation of CNG channel mRNA.

Chronomedicine and type 2 diabetes: shining some light on melatonin

“…High-throughput analysis of mRNA abundance with RNA sequencing (RNA-seq) has confirmed MT1 and MT2 expression in human islets, though equal abundance of transcript for each was reported in alpha and beta cells [107]. In the pancreatic islet, melatonin regulates a bevy of cellular activity and gene expression [108][109][110][111]. The observation that melatonin has sleep-promoting effects occurred almost in parallel with the discovery that this hormone had 'insulin-like' activity.…”

“…Melatonin can also act through G i -coupled MT2 receptors in INS-1 cells to lower intracellular Ca 2+ levels [110,113], which is also predicted to reduce insulin secretion. Finally, melatonin can act through G q -coupled MT2 receptors to stimulate phospholipase C (PLC) and inositol triphosphate (IP3) activity [114], which is expected to boost insulin secretion.…”

The insulin–melatonin antagonism: studies in the LEW.1AR1-iddm rat (an animal model of human type 1 diabetes mellitus)

“…Recently, it became possible to identify the intracellular signal cascades of pancreatic beta cells that are melatonin-dependent. Our own previous investigations have shown that the MT 1 and MT 2 receptors of pancreatic beta cells are linked to adenylate cyclasecAMP [2], the phospholipase C inositol-1,4,5-triphosphate (IP 3 ) [12,13] and the guanylate cyclase-cGMP pathways [14,15]. It was confirmed that melatonin inhibits the cAMP and cGMP pathways and consequently decreases insulin release [2,8,14,15].…”

The role of melatonin in diabetes: therapeutic implications

“…Melatonin activates MT2 receptor that inhibits the second messenger cGMP and suppresses secretion of insulin through pancreatic β-cells (49,50 tially turns on CREB and/or C/EBP (CCAAT enhancer-binding protein. The MT2-receptor also affects the second messenger cAMP in an inhibitory manner.…”