Membrane Melatonin Receptors Activated Cell Signaling in Physiology and Disease

Abstract

The pineal hormone melatonin has attracted great scientific interest since its discovery in 1958. Despite the enormous number of basic and clinical studies the exact role of melatonin in respect to human physiology remains elusive. In humans, two high-affinity receptors for melatonin, MT1 and MT2, belonging to the family of G protein-coupled receptors (GPCRs) have been cloned and identified. The two receptor types activate Gi proteins and MT2 couples additionally to Gq proteins to modulate intracellular events. The individual effects of MT1 and MT2 receptor activation in a variety of cells are complemented by their ability to form homo- and heterodimers, the functional relevance of which is yet to be confirmed. Recently, several melatonin receptor genetic polymorphisms were discovered and implicated in pathology-for instance in type 2 diabetes, autoimmune disease, and cancer. The circadian patterns of melatonin secretion, its pleiotropic effects depending on cell type and condition, and the already demonstrated cross-talks of melatonin receptors with other signal transduction pathways further contribute to the perplexity of research on the role of the pineal hormone in humans. In this review we try to summarize the current knowledge on the membrane melatonin receptor activated cell signaling in physiology and pathology and their relevance to certain disease conditions including cancer.

Keywords: G protein-coupled receptors; MAPK/ERK signaling; diseases; melatonin; single-nucleotide polymorphisms (SNPs).

Figure 1

Melatonin receptor-activated signaling pathways. AC—adenylate cyclase; GC—guanylate cyclase; PLCβ—phospholipase C-β; IP3—inositol triphosphate; PI3K—phosphoinositide 3-kinase; PDK—phosphoinositide-dependent kinase; PKC -protein-kinase C; pAkt—phosphorylated protein-kinase B; cAMP—cyclic adenosine monophosphate; PKA—protein-kinase A; pCREB—phosphorylated cAMP response element binding protein; cGMP—cyclic guanosine monophosphate; PKG—protein-kinase G; pERK1/2—phosphorylated extracellular signal-regulated protein kinases 1 and 2.

Figure 2

Melatonin and carbohydrate disturbances—pathophysiological mechanisms. T2DM—diabetes mellitus type 2; GLP-1—glucagon like peptide 1; MT1—melatonin receptor type 1; MT2—melatonin receptor type 2; ↑—increase; ↓—decrease; ↕—modulate.