The mammalian retina contains circadian clocks that regulate multiple aspects of retinal function by driving circadian rhythms of gene expression, photoreceptor outer segment membrane turnover, and visual sensitivity. Previous work has shown that melatonin acting via g protein-coupled melatonin receptors (MTRs) plays a key role in the regulation of a wide variety of retinal circadian rhythms and melatonin is involved in the modulation of retinal cell viability during aging. In the present application we will further investigate the effect of MTR removal on the retina by using melatonin proficient mice (C3H-f+/+) mouse in which the two different types of g- protein coupled melatonin receptors (MTRs) have been removed. These new animal models developed in our laboratory provide a unique and powerful tool with which to investigate the role of melatonin and MTRs in the retina. Our preliminary data suggest that melatonin action within the some retinal cells is likely to be mediated via the formation of melatonin receptor 1 and 2 heteromers (MTRh). The present application comprises three specific aims.
In specific aim 1, we will determine whether melatonin receptor type 1 and melatonin receptor type 2 form heteromers in retinal cells.
In Specific aim 2, we will investigate the role of melatonin and its associated receptors in the regulation of the daily rhythms in disc shedding in melatonin proficient mice and melatonin receptor knock-out mice. Finally, in specific aim 3 we will determine whether administration of exogenous melatonin increase the sensitivity of the retina to light-induced damage via activation of MTRs and we will dissect the signaling pathways activate by melatonin in the photoreceptor and RPE cells. In our research, we will use a wide array of new and technologically advanced techniques, such as quantitative real time Q-RT-PCR, Bioluminescence Resonance Energy Transfert (BRET), laser capture dissecting microscopy, and microarray analysis.

Public Health Relevance

The characterization of the action of melatonin and its associated receptors may provide new and important insights on the mechanisms of action of melatonin in the eye and more in general in the rest of the body. The experiments proposed in our application will generate data that may lead to the development of new therapeutic tools to treat or prevent disease states associated with dysfunction of the melatonergic system.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Greenwell, Thomas
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Morehouse School of Medicine
Schools of Medicine
United States
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Tosini, Gianluca; Owino, Sharon; Guillaume, Jean-Luc et al. (2014) Understanding melatonin receptor pharmacology: latest insights from mouse models, and their relevance to human disease. Bioessays 36:778-87
McMahon, Douglas G; Iuvone, P Michael; Tosini, Gianluca (2014) Circadian organization of the mammalian retina: from gene regulation to physiology and diseases. Prog Retin Eye Res 39:58-76
Hiragaki, Susumu; Baba, Kenkichi; Coulson, Elise et al. (2014) Melatonin signaling modulates clock genes expression in the mouse retina. PLoS One 9:e106819
Iuvone, P Michael; Boatright, Jeffrey H; Tosini, Gianluca et al. (2014) N-acetylserotonin: circadian activation of the BDNF receptor and neuroprotection in the retina and brain. Adv Exp Med Biol 801:765-71
Dortch-Carnes, Juanita; Tosini, Gianluca (2013) Melatonin receptor agonist-induced reduction of SNP-released nitric oxide and cGMP production in isolated human non-pigmented ciliary epithelial cells. Exp Eye Res 107:1-10
Baba, Kenkichi; Benleulmi-Chaachoua, Abla; Journe, Anne-Sophie et al. (2013) Heteromeric MT1/MT2 melatonin receptors modulate photoreceptor function. Sci Signal 6:ra89