Fig. 8

Melatonin’s receptors and mechanism of action. Melatonin can exert its various actions on cells through receptor-mediated and non-receptor mediated actions. Melatonin receptors are dispersed in the cytoplasm as MT3 receptors which are the cytosolic enzyme quinone reductase 2 (QR2), in the nucleus as the retinoid-related orphan (ROR) receptors, and on the cell membrane. On the cell membrane, melatonin acts through membrane-related G protein-coupled receptors (GPCRs) called MT1 and MT2. When melatonin binds to the Gi coupled receptors, the alpha subunit seperates from the beta and gamma subunits, with the conversion of the attached guanosine diphosphate (GDP) to guanosine triphosphate (GTP). This inhibits adenyle cyclase (AC) and the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP response element-binding protein (CREB) pathway. Also, the binding of melatonin to the Gi coupled receptors can inhibit the guanylate cyclase (GC)/cyclic guanosine monophosphate (cGMP)/protein kinase G (PKG) pathway. The activation of the Gq-coupled receptors activates phospholipase C (PLC), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol triphosphate (IP3) and 1,2-diacylglycerol (DAG), which increases Ca⁺²levels and activates calmodulin (CaM) and CaM kinase signaling