FIGURE 3.

Melatonin signaling pathways are summarized in this figure. Both MT1 and MT2 belong to the GPCRs family of receptors. Melatonin also crosses the plasma membrane via passive diffusion. Upon the attachment of melatonin to MT1 and MT2, different effectors including PKC, PLCβ, and PKA are recruited as second messengers to trigger downstream signaling pathways. For subsequent events, the melatonin-MT1 complex linked α_q, α_i, β, and γ subunits to activate IP3 and intracellular accumulation of Ca⁺² after its release from the endoplasmic reticulum. Ca⁺² phosphorylates both PKC and ERK1/2. MT1 receptor also acts through membrane adenyl cyclase, which blocks the phosphorylation of CREB by activation of cAMP and PKC. Melatonin binding to MT2 activates the adenyl cyclase and leads to CREB inactivation. Melatonin promotes conformational changes in MT2 and activation of α_i subunit leads to stimulation of PKG via guanylate cyclase. Also, MT2 engages PKC and ErK1/2 complexes. Melatonin crosses the plasma membrane via passive diffusion and transporters and activates both mitochondrial MT1 and 2 thereby reducing the escape of cytochrome C into the cytosol. Other possible melatonin receptors include cytosolic quinone reductase 2 which activates nuclear RORα/RZR. Mel, melatonin; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; MT, melatonin receptor; PKC, protein kinase C; PKA, protein kinase A; CREB, cAMP response element-binding protein; IP3, inositol trisphosphate; and PDK, pyruvate dehydrogenase kinase.