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D. Gu, Z. Li, G. Acland, G. Aguirre; Clinical Light Exposure, Photoreceptor Degeneration and AP-1 Activation in T4R Rhodopsin Mutant Dog Retinas. Invest. Ophthalmol. Vis. Sci. 2007;48(13):581.
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To gain the better understanding of the molecular mechanisms of the clinical light induced retinal degeneration in T4R RHO mutant dogs. We have examined and analyzed the AP-1 activity, composition and post-translation modification of AP-1 protein, and activation of ERK/MAPK pathways.
Wild type, T4R RHO mutant dogs were dark adapted overnight. Both eyes were dilated with mydriatics; right eye was light occluded and the fundus of the left eye photographed (~15-17 overlapping frames) using a Kowa RC-2 fundus camera. Dogs remained in the dark until sacrificed at different time points after exposure. AP-1 DNA binding activity and protein composition was determined by electrophoretic mobility shift assays (EMSA) and super-shift EMSA. Immunoblotting was performed to examine components of AP-1 protein and MAPKs pathways.
Significantly increased AP-1 activity was observed in the light exposed T4R RHO mutant dog retinas by 1 hour after exposure, and remained elevated up to 6 hours. Non-exposed control retinas had AP-1 levels comparable to the wild type. Phosphorylatied c-Fos protein was identified in the light exposed T4R RHO mutant retinas, and ERK1/2 activation was detected at 1 hour following light exposure. These biochemical events, activation of ERK1/2, c-Fos phosphorylation and induction of AP-1 DNA binding activity, prior to the onset of light induced photoreceptor degeneration, and have a similar magnitude and time course. With light exposure, a modification of AP-1 protein composition in T4R RHO mutant dog retinas was observed.
The activation of T4R mutant rhodopsin by clinical light exposure may initiate ERK/MAPK pathway; c-Fos may be phosphorylated by activated ERK1/2 and induce AP-1 activity. AP-1 may play a important role in the photoreceptor degeneration process
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