Melatonin Receptor Signaling: Impact of Receptor Oligomerization on Receptor Function

Abstract The melatonin receptor subfamily is composed of three members, MT 1 and MT 2 , which are binding to melatonin, and GPR50, which shows high sequence homology to MT 1 and MT 2 but does not bind to melatonin or any other known ligand. An interesting feature of these receptors is their capacity to form homo- and heteromers between each other and also with other GPCRs. The following heteromers have been described: MT 1 /MT 2 , MT 1 /GPR50, and heteromers composed of MT 2 and the serotonin 5-HT 2c receptor or the orphan GPR61, GPR62, and GPR135 receptors. These heteromers represent novel pharmacological entities as they exhibit functional properties that are different from those of the corresponding homomers. Formation of several of these heteromers has been confirmed in tissues. MT 2 /5-HT 2c heteromers are targeted by the clinically relevant antidepressant agomelatine, and MT 1 /MT 2 heteromers regulate nocturnal retinal light sensitivity. Here, we resume our current knowledge on melatonin receptor heteromerization and discuss how it contributes to the diversification of the function of melatonin receptors.