The first event in light perception is capture of a photon by an opsin visual-pigment within a photoreceptor cell of the retina. This triggers a chemical change in the retinaldehyde chromophore, a small molecule related to vitamin A contained within each opsin pigment. This can be likened to the tripping a mouse trap. Before light sensitivity can be restored to the `bleached'pigment, the retinaldehyde chromophore must be chemically regenerated, i.e., the mouse trap must be reset. This is accomplished by a multi-step enzyme pathway in the retinal pigment epithelium (RPE), a layer of cells adjacent to the retina. Mutations in the gene for almost every protein within this enzyme pathway cause some type of inherited blinding disease. This indicates the importance of the `visual cycle'to vision in humans. Over the years, evidence has accumulated that another type of cell, the Muller cell, located within the retina, also participates in the regeneration of visual chromophore. In particular, Muller cells may assist in the regeneration of chromophore destined for cone photoreceptors. Cones provide high-resolution color vision in bright light, and are critical to normal sight in humans. Almost nothing is known about how Muller cells regenerate visual chromophore, and what are the relative contributions of RPE versus Muller cells in rod-dominant species, such as humans. The current application addresses these questions using a `two-pronged'approach. One set of experiments seeks to identify each protein responsible for the vitamin A-processing activities detected in retina homogenates. Another set of experiments seeks to define the function of each vitamin A-processing protein previously identified in Muller cells. Information from these approaches should converge to yield a clear picture about the role of Muller cells in visual-pigment regeneration.
Light perception is mediated by visual pigments in the eye. For sustained vision, these pigments must be continuously regenerated. This project is to study the biochemical mechanisms of visual-pigment regeneration. Defects in pigment regeneration cause inherited blinding diseases. The project will help us understand how these genetic diseases arise.
|Kaylor, Joanna J; Cook, Jeremy D; Makshanoff, Jacob et al. (2014) Identification of the 11-cis-specific retinyl-ester synthase in retinal Müller cells as multifunctional O-acyltransferase (MFAT). Proc Natl Acad Sci U S A 111:7302-7|
|Kaylor, Joanna J; Yuan, Quan; Cook, Jeremy et al. (2013) Identification of DES1 as a vitamin A isomerase in Muller glial cells of the retina. Nat Chem Biol 9:30-6|
|Kawaguchi, Riki; Yu, Jiamei; Ter-Stepanian, Mariam et al. (2011) Receptor-mediated cellular uptake mechanism that couples to intracellular storage. ACS Chem Biol 6:1041-51|
|Blakeley, Lorie R; Chen, Chunhe; Chen, Ching-Kang et al. (2011) Rod outer segment retinol formation is independent of Abca4, arrestin, rhodopsin kinase, and rhodopsin palmitylation. Invest Ophthalmol Vis Sci 52:3483-91|
|Linton, Jonathan D; Holzhausen, Lars C; Babai, Norbert et al. (2010) Flow of energy in the outer retina in darkness and in light. Proc Natl Acad Sci U S A 107:8599-604|
|Travis, Gabriel H; Kaylor, Joanna; Yuan, Quan (2010) Analysis of the retinoid isomerase activities in the retinal pigment epithelium and retina. Methods Mol Biol 652:329-39|
|Yuan, Quan; Kaylor, Joanna J; Miu, Anh et al. (2010) Rpe65 isomerase associates with membranes through an electrostatic interaction with acidic phospholipid headgroups. J Biol Chem 285:988-99|
|Jin, Minghao; Li, Songhua; Nusinowitz, Steven et al. (2009) The role of interphotoreceptor retinoid-binding protein on the translocation of visual retinoids and function of cone photoreceptors. J Neurosci 29:1486-95|
|Radu, Roxana A; Hu, Jane; Peng, Jennifer et al. (2008) Retinal pigment epithelium-retinal G protein receptor-opsin mediates light-dependent translocation of all-trans-retinyl esters for synthesis of visual chromophore in retinal pigment epithelial cells. J Biol Chem 283:19730-8|
|Radu, Roxana A; Yuan, Quan; Hu, Jane et al. (2008) Accelerated accumulation of lipofuscin pigments in the RPE of a mouse model for ABCA4-mediated retinal dystrophies following Vitamin A supplementation. Invest Ophthalmol Vis Sci 49:3821-9|
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