Melatonin receptors, heterodimerization, signal transduction and binding sites: what's new?

Abstract

Melatonin is a neurohormone that has been claimed to be involved in a wide range of physiological functions. Nevertheless, for most of its effects, the mechanism of action is not really known. In mammals, two melatonin receptors, MT 1 and MT 2 , have been cloned. They belong to the G-protein-coupled receptor (GPCR) superfamily. They share some specific short amino-acid sequences, which suggest that they represent a specific subfamily. Another receptor from the same subfamily, the melatoninrelated receptor has been cloned in different species including humans. This orphan receptor also named GPR50 does not bind melatonin and its endogenous ligand is still unknown. Nevertheless, this receptor has been shown to behave as an antagonist of the MT 1 receptor, which opens new pharmacological perspectives for GPR50 despite the lack of endogenous or synthetic ligands. Moreover, MT 1 and MT 2 interact together through the formation of heterodimers at least in cells transfected with the cDNA of these two receptors. Lastly, signalling complexes associated with MT 1 and MT 2 receptors are starting to be deciphered. A third melatonin-binding site has been purified and characterized as the enzyme quinone reductase 2 (QR2). Inhibition of QR2 by melatonin may explain melatonin's protective effect that has been reported in different animal models and that is generally associated with its well-documented antioxidant properties.

Convergence of Melatonin and Serotonin (5-HT) Signaling at MT2/5-HT2C Receptor Heteromers

“…The absence of 5-HT-promoted IP production was confirmed in cells expressing 5-HT 2C -S138N and MT 2 (Fig. 5B).…”

“…The monoamine serotonin (5-HT) 2 is derived from dietary tryptophan, which is transformed into 5-HT in diverse clusters of neurons in the gut and brain. 5-HT exerts its actions via 14 classes of receptors, which are broadly expressed in peripheral tissues and the central nervous system (1).…”

“…Conversely, although the neurohormone melatonin is derived from 5-HT, it is mainly produced by the pineal gland in a circadian pattern under the control of hypothalamic nuclei, attaining peak levels during the night. Melatonin binds with high affinity to MT 1 and MT 2 receptors and with moderate affinity to the enzyme quinone reductase 2 (2). Both MT 1 and MT 2 receptors as well as all 14 classes of 5-HT receptor (except 5-HT 3 ) belong to the G protein-coupled receptor (GPCR) superfamily.…”

Implication des mutations du récepteur de la mélatonine MT2dans la survenue du diabète de type 2

“…Chez les rongeurs, la MLT inhibe la sécrétion d'insuline des cellules β en bloquant les niveaux intracellulaires d'AMP cyclique (AMPc) et de GMP cyclique (GMPc). Une telle signalisation est en accord avec des études qui montrent que, dans des cellules transfectées, les deux récepteurs MT 1 et MT 2 induisent une réduction du niveau d'AMPc [26], et le récepteur MT 2 celle du GMPc [27]. Cependant, dans les îlots humains, la MLT ne semble pas inhiber la production de ces deux seconds messagers [24].…”

Potential Modulation of Disease Activity Indices and Inflammatory Biomarkers in Patients With Active Inflammatory Bowel Disease on Melatonin Adjuvant Therapy

“…Melatonin exerts its physiological action through specific membrane receptors, which are melatonin-1 receptor (MT1), MT2, and MT3 [5]. These receptors can be located in the GIT and their participation in the control of GI inflammation, motility, and pain has been stated in several basic and clinical studies [3,6].…”