The neurohormone, melatonin, is a primary output signal of the circadian clock in retinal photoreceptors. In the retina, melatonin acts as a paracrine signal of darkness by activating specific receptors that ultimately leads to increased sensitivity to light. It facilitates dark adaptation and likely coordinates other diumal events that occur in the retina such as photoreceptor outer segment disc shedding. In addition, melatonin increases the degree of light-induced photoreceptor cell death. The cellular location of the melatonin receptor subtypes and the physiological responses to melatonin receptor binding are important factors that determine the influence of melatonin on the normal health and function of the retina. The long-term goal of this research is to understand the molecular mechanisms of action and the function of melatonin in the retina and the role of circadian sitnals in photoreceptor physiology and disease. The retina of the frog Xenopus laevis has been an exceptional in vitro model system to study retinal melatonin synthesis and function, and RNA encoding three melatonin receptor subtypes is expressed both in the neural retina, including the photoreceptors, and retinal pigment epithelium (RPE) of Xenopus retina. Also, recent advancements in transgenic Xenopus technology have greatly enhanced the utility of this frog model in the study of cell-specific gene expression. The goals of this proposal are to 1) direct rod photoreceptor-specific over-expression of each of the three melatonin receptor subtypes in transgenic Xenopus, and to compare the cellular responses to applied melatonin, and 2) direct Melic melatonin receptor subtype cell-specific over-expression in transgenic Xenopus, and identify all retinal cells that express the transgene by reporter gene fluorescence combined with immunocytochemistry of known retinal proteins. Disruption of circadian rhythms may contribute significantly to the photoreceptor cell death in some degenerative retinal diseases, and melatonin may play a pivotal role in coordinating retinal circadian events. Discovering the molecular mechanisms of melatonin action may therefore provide a greater understanding of the role of circadian signals in environmentally- and genetically- induced photoreceptor degenerations.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Small Research Grants (R03)
Project #
1R03EY013686-01
Application #
6411901
Study Section
Special Emphasis Panel (ZEY1-VSN (04))
Program Officer
Mariani, Andrew P
Project Start
2002-02-07
Project End
2005-01-31
Budget Start
2002-02-07
Budget End
2003-01-31
Support Year
1
Fiscal Year
2002
Total Cost
$146,500
Indirect Cost
Name
University of Oklahoma Health Sciences Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
937727907
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
Wiechmann, Allan F; Chignell, Colin F; Roberts, Joan E (2008) Influence of dietary melatonin on photoreceptor survival in the rat retina: an ocular toxicity study. Exp Eye Res 86:241-50
Wiechmann, Allan F; Summers, Jody A (2008) Circadian rhythms in the eye: the physiological significance of melatonin receptors in ocular tissues. Prog Retin Eye Res 27:137-60
Rada, Jody A Summers; Wiechmann, Allan F (2006) Melatonin receptors in chick ocular tissues: implications for a role of melatonin in ocular growth regulation. Invest Ophthalmol Vis Sci 47:25-33
Prada, Claudia; Udin, Susan B; Wiechmann, Allan F et al. (2005) Stimulation of melatonin receptors decreases calcium levels in xenopus tectal cells by activating GABA(C) receptors. J Neurophysiol 94:968-78
Wiechmann, Allan F; Udin, Susan B; Summers Rada, Jody A (2004) Localization of Mel1b melatonin receptor-like immunoreactivity in ocular tissues of Xenopus laevis. Exp Eye Res 79:585-94
Wiechmann, Allan F; Vrieze, Melissa J; Dighe, Radhika et al. (2003) Direct modulation of rod photoreceptor responsiveness through a Mel(1c) melatonin receptor in transgenic Xenopus laevis retina. Invest Ophthalmol Vis Sci 44:4522-31
Wiechmann, Allan F; Rada, Jody A (2003) Melatonin receptor expression in the cornea and sclera. Exp Eye Res 77:219-25
Wiechmann, Allan F (2003) Differential distribution of Mel(1a) and Mel(1c) melatonin receptors in Xenopus laevis retina. Exp Eye Res 76:99-106