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Gianluca Tosini, Kenkichi Baba; Regulation of Ocular Functions by Dopamine and Melatonin. Invest. Ophthalmol. Vis. Sci. 2014;55(13):362.
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Previous studies have shown that the retina, the retinal pigment epithelium (RPE) and the cornea contain a circadian clock that controls the circadian rhythms in PER2::LUC bioluminescence. Additional studies have indicated that only in the retina the PER2::LUC rhythm can be phase-shifted by light, thus suggesting that other signals are used by the retina to entrain the circadian rhythms in other ocular structures. Melatonin (MLT) and dopamine (DA) are known to be the key molecules to regulated retinal circadian rhythms. In this study we investigated the role of DA and MLT to and their associated receptors in the regulation of RPE and cornea circadian rhythm.
Eyes were obtained from PER2::LUC mice, the eye-cups were dissected, and the retina, RPE-choroid and cornea were cultured at 37 oC with 199 medium containing 0.1mM D-Luciferin K salt. The bioluminescence emitted by these tissues was measured using a LumiCycle. After 3-4 days of culture, DA (100uM), MLT (100nM) and DA or MLT receptor agonists were added to the culture at different circadian times, and the recording was continued another 5 days. Activity of focal adhesion kinase (pFAK/FAK) in control and D2R knock-out mice was measured by western blotting whereas central corneal thickness (CCT) in mice lacking melatonin receptors was measured using a ultrasound pachometer, Corneo-Gage Plus 1AS.
Administration of DA, but not MLT, phase-shifted PER2::LUC bioluminescence rhythm in the RPE-choroid. Sumanirole (D2R agonist) induced a significant phase-shift during the late night -early subjective day, whereas PD168077 (D4R agonist) did not produce a significant phase-shift of the PER2::LUC bioluminescence rhythm. Conversely, administration of MLT, but not DA, phase-shifted PER2::LUC bioluminescence rhythm in the cornea. Mice lacking D2R signaling showed a change in the timing of the daily rhythm in FAK activation whereas removal MLT signaling affected the daily rhythm in CCT.
Our data indicate that DA via D2 receptors can phase-shift the circadian rhythm in PER2::LUC bioluminescence rhythm in the mouse RPE, whereas MLT can phase-shift the circadian rhythm in PER2::LUC bioluminescence in the cornea. Thus indicating that the retina uses DA and MLT to entrain other tissues within the eye. Our data also indicate that activation of these signaling pathways is the correct timing of circadian functions in these tissues.
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