Melatonin: an underappreciated player in retinal physiology and pathophysiology

Abstract

In the vertebrate retina, melatonin is synthesized by the photoreceptors with high levels of melatonin at night and lower levels during the day. Melatonin exerts its influence by interacting with a family of G-protein-coupled receptors that are negatively coupled with adenylyl cyclase. Melatonin receptors belonging to the subtypes MT(1) and MT(2) have been identified in the mammalian retina. MT(1) and MT(2) receptors are found in all layers of the neural retina and in the retinal pigmented epithelium. Melatonin in the eye is believed to be involved in the modulation of many important retinal functions; it can modulate the electroretinogram (ERG), and administration of exogenous melatonin increases light-induced photoreceptor degeneration. Melatonin may also have protective effects on retinal pigment epithelial cells, photoreceptors and ganglion cells. A series of studies have implicated melatonin in the pathogenesis of age-related macular degeneration, and melatonin administration may represent a useful approach to prevent and treat glaucoma. Melatonin is used by millions of people around the world to retard aging, improve sleep performance, mitigate jet lag symptoms, and treat depression. Administration of exogenous melatonin at night may also be beneficial for ocular health, but additional investigation is needed to establish its potential.

Figure 1

Melatonin synthesis starts with up-take of the circulating amino acid tryptophan and the subsequent 5-hydroxylation by tryptophan hydroxylase. 5-Hydroxytryptophan is then converted to serotonin by the action of aromatic L-amino acid decarboxylase. Serotonin is acetylated by arylalkylamine N-acetyltransferase (AANAT) to N-acetylserotonin, which is subsequentely O-methylated and converted to melatonin by acetylserotonin methyltransferase (ASMT), which is also known as hydroxyindole-O-methyltransferase. The metabolism of retinal melatonin illustrated on the right has been demonstrated for Xenopus, reptiles, teleost fish, and chicken but not in mammals (see text).

Figure 2

Regulation of retinal melatonin levels by light and the circadian clock. At night in darkness cAMP levels are elevated, activating PKA, which induces Aanat gene transcription and phosphorylates AANAT protein. Phosphorylated AANAT (pAANAT) associates with 14-3-3 proteins, which activate and stabilize the enzyme resulting in increased conversion of serotonin to N-acetylserotonin, and ultimately to melatonin. Light exposure decreases cAMP levels resulting in dephosphorylation of AANAT and its subsequent degradation by proteasomal degradation. The circadian clock controls melatonin levels by directly regulating Aanat transcription and by gating the cAMP signaling cascade.

Figure 3

Melatonin receptors are expressed in many retinal cell types. Activation of these receptors may modulate several retinal functions such as: disk shedding, retinal cell viability; visual sensitivity; and dopamine levels and metabolism. RPE=retinal pigmented epithelium; R= rod photoreceptors; B= bipolar cells; A= amacrine cells; GC= retinal ganglion cells.