Cone Viability Is Affected by Disruption of Melatonin Receptors Signaling

Abstract

PurposePrevious studies have demonstrated that melatonin has an important role in the modulation of photoreceptor viability during aging and may be involved in the pathogenesis of age-related macular degeneration.This hormone exerts its influence by binding to G-protein coupled receptors named melatonin receptor 1 (MT1) and 2 (MT2). Melatonin receptors 1 and 2 activate a wide variety of signaling pathways.MethodsMelatonin-proficient mice (C3H/f+/+) and melatonin-proficient mice lacking MT1 or MT2 receptors (MT1−/− and MT2−/−) were used in this study. Mice were killed at the ages of 3 and 18 months, and photoreceptor viability was determined by counting nuclei number in the outer nuclear layer (ONL). Cones were identified by immunohistochemistry using peanut agglutinin (PNA) and green/red and blue opsin antibodies. Protein kinase B (AKT) and forkhead box O (FOXO1) were assessed by Western blotting and immunohistochemistry.ResultsThe number of nuclei in the ONL was significantly reduced in C3Hf+/+, MT1−/−, and MT2−/− mice at 18 months of age with respect to 3-month-old animals. In 18-month-old MT1−/− and MT2−/− mice, but not in C3H/f+/+, the number of cones was significantly reduced with respect to young MT1−/− and MT2−/− mice or age-matched C3H/f+/+. In C3H/f+/+, activation of the AKT-FOXO1 pathway in the photoreceptors showed a significant difference between night and day.ConclusionsOur data indicate that disruption of MT1/MT2 heteromer signaling induces a reduction in the number of photoreceptors during aging and also suggest that the AKT-FOXO1 survival pathway may be involved in the mechanism by which melatonin protects photoreceptors.

Removal of clock gene Bmal1 from the retina affects retinal development and accelerates cone photoreceptor degeneration during aging

“…Finally, it is worth noting that disruption of the retinal melatonin system (a key circadian output in the eye) also produces a significant reduction in the number of cone photoreceptors (about 30%) during aging (25). Hence, it appears that a significant feature of the dysfunction of the retinal circadian system produced by genetic mutation of the clock genes or its circadian output is the effect on cone viability.…”

The Retina and Other Light-sensitive Ocular Clocks

“…For example, it has long been known that the corneal epithelium exhibits high amplitude rhythms of mitotic activity (Scheving & Pauly, 1974, Scheving et al, 1974) that are likely controlled locally. The same can be said for the ciliary body and the findings that intraocular pressure, aqueous humor flow, and aqueous cAMP levels all exhibit circadian rhythms (Boyd & McLeod, 1964, Rowland et al, 1986, Smith & Gregory, 1989) that are regulated through a noradrenergic system (Eakins & Eakins, 1964, Gianesini et al, 2016, Yoshitomi & Gregory, 1991). It is possible for example, that such regulation involves synchronization of a local clock in the ciliary body that in turn regulates secretion of aqueous humor.…”

“…In addition, melatonin, which is normally high at night, potentiates light damage (Wiechmann & O'Steen, 1992) and its antagonist, luzindole, is neuroprotective for photoreceptors (Sugawara et al, 1998). Furthermore, loss of both the MT1 and MT2 melatonin receptors ( MTNR1A and MTNR1B ) results in attrition of cones in older mice (Gianesini et al, 2016). In contrast to its impact on photoreceptors, melatonin and its type 1 receptor ( MT1, MTNR1A ) are important in maintaining ganglion cells as loss of either melatonin or MT1 receptors results in an age related decline in ganglion cell numbers and an increase in intra-ocular pressure (Alcantara-Contreras et al, 2011, Baba et al, 2009).…”

Update on melatonin receptors: IUPHAR Review 20

“…Such a result also indicates that MT 1 and MT 2 receptors form heterodimers in mouse photoreceptors (Baba et al, ). Further studies have also demonstrated that removal of MT receptors in addition affects the viability of the photoreceptors and retinal ganglion cells during aging (Baba et al, ; Alcantara‐Contreras et al, ; Gianesini et al, ) as well as corneal biology (Baba et al, ).…”