Anales RANF

Melatonin and melanopsin in the eye: friends or foes? @Real Academia Nacional de Farmacia. Spain 53 cells, the TRPV4 channel was stimulated since this protein is sensitive to mechanical pressure. The activation of this channel leaded to and increment of both melatonin levels extracellularly and an increase in the expression of the protein AANAT (48, 49). Other studies showed that the activation of this channel has a short term effect when activated, similar to a sudden increase of IOP, where it phosphorylate the enzyme AANAT, hence protecting it from degradation and leading to an increment of melatonin (50, 51). TRPV4 was silenced in the non-pigmented ciliary body epithelial cells to confirm the effect of melatonin increment, confirming the importance of this channel in regulating melatonin synthesis in the ciliary processes (52). This difference in melatonin levels in the aqueous humor was also reported for other diseases. A study analyzing melatonin levels in patients with proliferative diabetic retinopathy showed that those patients had a significant increase of melatonin in the aqueous humor compared to healthy subjects, and interestingly, this increment was not seen in serum samples taken from the same patients. This indicates that melatonin synthesis is increased in the eye only and its origin is not the circulating melatonin from the pineal gland (53). In fact, in a different study, melatonin decreased in blood serum of patients with type 2 diabetes with cardiac autonomic neuropathy (54), also urinary 6-sulfatoxymelatonin level in were found lower in patients with diabetic retinopathy with type 2 diabetes (55). All the mentioned studies are evidence of a possible melatonin modification or changes in the eye due to ocular diseases. However, a different perspective of melatonin regulation has rose due to a public serious issue; light pollution. Light at night is currently associated to several pathologies, and it is considered as a possible risk factor to develop many diseases, starting from obesity to a more serious pathologies such as cancer (56, 57). Light can disrupt the circadian rhythm and when it activates the non- image forming photoreceptor situated in a small number of the retinal ganglion cells, melanopsin: It directly projects its signals to the pineal gland to shut-off melatonin synthesis, and it is associated directly or indirectly to a wide range of pathologies (58). 3. MELANOPSIN, THE HIDDEN RECEPTOR IN OUR EYES In the 1920s, a Harvard university graduate student, Clyde Keeler, discovered that blind mice due to rod and cone dystrophy, can still respond to ambient light by pupil constriction, and moreover, they conserved their ability for photo-entrainment (59). This was the first evidence of the presence of a different photoreceptor in the eye, however, since the retina is an extensively studied tissue, with all its layers, rods and cones were the only photoreceptors recognized by scientists for decades after Keeler´s observation. Nonetheless, all posterior studies confirmed that the eyes are essential as the primary source of light information for photo-entrainment, and eye loss in mammals abolishes this characteristic (60). Decades after Keeler´s discovery, in 2000, the scientist Provencio identified a small subclass of retinal ganglion cells which are photosensitive. This is because they contain a photopigment, melanopsin, sensitive to short wave length content of light (corresponding to blue light) (1). In fact, this photoreceptor was identified earlier in dermal melanophores, eye, and the brain of Xenopus laevis , but it was not found in extra-ocular regions in mammals (61). This discovery explained the reason why rodless and coneless eyes can still react to light. Interestingly, this photopigment have different characteristics than ones found in mammals. For instance, it presents greater homology to invertebrate opsin than those of vertebrate; melanopsin in mammals belongs to the rhabdomeric receptors unlike the ciliary receptors in rods and cones (62). Moreover, this photoreceptor depolarize in reaction to light, whereas rods and cone hyperpolarize. Moreover studies using pharmacological approaches suggested the biochemical phototransduction cascade to be similar to invertebrate rhabdomeric photoreceptors acting through G q protein coupled opsin (63). After light stimulation, the photopigment of the intrinsically photosensitive retinal ganglion cells (ipRGC) triggers signalling, presumably, through Gq/11-class G- superfamily, which in turn activates a phospholipase C (PLC) (Fig. 3), provoking the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) in the membrane generating inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) and the later increase in cytoplasmic Ca 2+ and ultimately causing membrane depolarization. Furthermore, the participation of TRP and TRPL channels, the Ca 2+ -permeable light-sensitive channels, made clear since treatments with a Ca 2+ chelator or a TRP channel blocker were able to reduce the light effect. Treating chicken primary retinal ganglion cells (RGCs) cultures with PLC inhibitors abolished the light-suppressive effect on 3 H-melatonin synthesis. These findings demonstrated the chemical components of the phototransduction cascade operating in vertebrate embryonic RGCs is involving a Gq-protein (64-66). When light reaches the inner retina and activate melanopsin containing ganglion cells, signals passes to different regions than the image forming pathway. They travel from the retina through the retinohypothalamic tract to the suprachiasmatic nucleus (SCN) and to the cervical superior ganglion and the pineal gland where light signals suppresses melatonin synthesis (Fig. 3) (67).