Understanding melatonin receptor pharmacology: latest insights from mouse models, and their relevance to human disease

Abstract

Melatonin, the neuro-hormone synthesized during the night, has recently seen an unexpected extension of its functional implications toward type 2 diabetes development, visual functions, sleep disturbances, and depression. Transgenic mouse models were instrumental for the establishment of the link between melatonin and these major human diseases. Most of the actions of melatonin are mediated by two types of G protein-coupled receptors, named MT1 and MT2 , which are expressed in many different organs and tissues. Understanding the pharmacology and function of mouse MT1 and MT2 receptors, including MT1 /MT2 heteromers, will be of crucial importance to evaluate the relevance of these mouse models for future therapeutic developments. This review will critically discuss these aspects, and give some perspectives including the generation of new mouse models.

Keywords: circadian rhythm; diabetes; melatonin; melatonin receptors; photoperiodism; retina; sleep.

Figure 1

Schematic drawing illustrating the regulation of pineal melatonin synthesis by the light/dark cycles via the SCN. During the daytime, the SCN inhibits melatonin synthesis, whereas at night the SCN sends a signal to the pineal to activate melatonin synthesis by increasing [over 100-fold] the transcription of the Aanat and then the activity of AANAT. AANAT converts serotonin to N-acetyl serotonin, and the Acetylserotonin N-Methyltransferase [ASMT] converts N-acetylserotonin to melatonin. ASMT transcription and activity also increases during the night, albeit to a lesser extent than AANAT.

Figure 1

Schematic drawing illustrating the regulation of pineal melatonin synthesis by the light/dark cycles via the SCN. During the daytime, the SCN inhibits melatonin synthesis, whereas at night the SCN sends a signal to the pineal to activate melatonin synthesis by increasing [over 100-fold] the transcription of the Aanat and then the activity of AANAT. AANAT converts serotonin to N-acetyl serotonin, and the Acetylserotonin N-Methyltransferase [ASMT] converts N-acetylserotonin to melatonin. ASMT transcription and activity also increases during the night, albeit to a lesser extent than AANAT.

Figure 2

Principal melatonin-receptor signaling pathways. Depending on the type of melatonin-receptor complexes present in cells (MT₁ homomers, MT₂ homomers, or MT₁/MT₂ heteromers), the depicted signaling pathways are activated upon melatonin stimulation. Thickness of the arrows represents the potency and efficiency of the activation of the pathway. DAG, diacylglycerol; ERK, extracellular signal-regulated kinase; IP3, inositol triphosphate; MUPP1, multi-PDZ domain protein 1; pCREB, phospho-cAMP-response element-binding protein; PLC, phospholipase C; PKA, protein kinase A; PKC, protein kinase C; RGS20, regulator of G protein signaling 20; sGC, soluble guanylyl cyclase.

Figure 3

Melatonin receptors are involved in the regulation of glucose metabolism. Evidence from in vitro and in vivo studies has demonstrated that signaling through melatonin receptors interacts with many facets of glucose metabolism. Within pancreatic islets, melatonin receptors are coupled to signaling pathways, which exert an inhibitory effect on insulin secretion from β-cells and a stimulatory effect on glucagon secretion from α-cells. In peripheral tissues, melatonin receptors appear to positively regulate glucose uptake within skeletal muscle and adipose tissue, and negatively regulate nocturnal glucose production by the liver.