Anales RANF

Melatonin and melanopsin in the eye: friends or foes? @Real Academia Nacional de Farmacia. Spain 51 Figure 1. Diagramatic resprestentation of melatonin synthesis in the pineal gland. Starting from tryptophan in the blood stream, which is converted into serotonin. The rise in AANAT activity results in an increase in the intracellular concentration of N-acetylserotonin which is further converted to melatonin by hydroxyindole-O-methyltransferase (modified from Klein, 1974). AANAT, arylalkylamine N - acetyltransferase; AC, adenylate cyclase; HIOMT, hydroxyindole- O- methyltransferase; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element-binding protein;NAS, N-acetyl 5-methoxytryptamine; NE, norepinephrine; PKA, protein kinase A. 2.1. Melatonin receptors and functions Melatonin has the ability to function through its receptors, but also it have direct actions as a free radical scavenger. Melatonin have two cloned and characterized membrane receptors in mammals, MT 1 and MT 2 . A putative MT 3 was suggested by several authors, and in some cases it was claimed to belong to the quinone reductase family, specifically, quinone reductase 2 (NQO2) (27, 28), although in other studies using different species through silencing this enzyme, melatonin still had functional properties (29). Melatonin receptors signalling pathways were extensively studied. In a canonical way, MT 1 and MT 2 stimulation would lead to adenylate cyclase (AC) inactivation in a G α i subunit process of the G protein coupled to the membrane receptor (30). When AC is inactivated, it would lead to a decrease in intracellular cAMP concentration, and finally a decrease in activated protein kinase A (PKA). The action of these receptors has been shown to inhibit forskolin-induced cAMP formation (31). However, melatonin receptors are also able to couple to different subtypes of G protein (32). Therefore the mentioned classical signal transduction is not the case in all cells and models, melatonin receptors activation also could lead to different intracellular signalling. For instance, some studies showed that MT 1 receptor activation would activate phospholipase C- α (PLC- α ) pathway (33); While MT 2 receptor, in addition to classical inhibition of AC, has been described in inhibition processes of the enzyme guanylate cyclase (GC) (Fig. 2) (34).