Melatonin Receptor

Melatonin (N-acetyl-5-methoxytryptamine) is a neurohormone which is mainly secreted from the pineal gland. Melatonin is a highly conserved molecule present not only in vertebrates but also in nonvertebrates such as bacteria, protists, fungi, macroalgae, and plants. The melatonin receptor subfamily consists of MT1 and MT2, whose natural ligand is melatonin, and GPR50, which does not bind to melatonin. The endogenous ligand of GPR50 is unknown, and GPR50 is therefore classified as orphan receptor. Recently three other orphan GPCRs, GPR61, GPR62, and GPR135, displaying ambiguous relationships to other GPCRs were proposed to belong to the melatonin receptor subfamily. 
Both melatonin receptors, MT1 and MT2, display high affinity for the natural ligand (low pM range) and both are predominantly coupled to Gi/o proteins. Thus, the main signaling pathway triggered by MT1 and MT2 involves the attenuation of adenylyl cyclase activity and consequent decrease of the intracellular levels of the second messenger cyclic adenosine monophosphate (cAMP). As a consequence, the activation of the protein kinase A (PKA) and the transcription factor CREB are also inhibited. The Gβγ subunits of Gi participate in the activation of the PI3K/Akt and PKC/ERK pathways. MT1 coupling to Gq activates phospholipase C (PLC) and increases intracellular calcium (Ca2+) levels. Melatonin also induces ß-arrestin recruitment to MT1, but ß-arrestin-dependent downstreaming signaling events are still unknown. Melatonin has been reported to counteract the production of reactive oxygen species (ROS), protecting thus against ROSinduced mitochondria damage.


1.Oishi A, et al. Int Rev Cell Mol Biol. 2018;338:59–77.