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J. Biol. Chem., Vol. 283, Issue 28, 19730-19738, July 11, 2008

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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^*

Roxana A. Radu, Jane Hu, Jennifer Peng, Dean Bok^¶1, Nathan L. Mata^||, and Gabriel H. Travis^¶**2

From the Jules Stein Eye Institute, Department of Neurobiology, ^¶Brain Research Institute, and ^**Department of Biological Chemistry, UCLA School of Medicine, Los Angeles, California 90095 and ^||Sirion Therapeutics, San Diego, California 92121

Visual perception begins with the absorption of a photon by an opsin pigment, inducing isomerization of its 11-cis-retinaldehyde chromophore. After a brief period of activation, the resulting all-trans-retinaldehyde dissociates from the opsin apoprotein rendering it insensitive to light. Restoring light sensitivity to apo-opsin requires thermal re-isomerization of all-trans-retinaldehyde to 11-cis-retinaldehyde via an enzyme pathway called the visual cycle in retinal pigment epithelial (RPE) cells. Vertebrates can see over a 10⁸-fold range of background illumination. This implies that the visual cycle can regenerate a visual chromophore over a similarly broad range. However, nothing is known about how the visual cycle is regulated. Here we show that RPE cells, functionally or physically separated from photoreceptors, respond to light by mobilizing all-trans-retinyl esters. These retinyl esters are substrates for the retinoid isomerase and hence critical for regenerating visual chromophore. We show in knock-out mice and by RNA interference in human RPE cells that this mobilization is mediated by a protein called "RPE-retinal G protein receptor" (RGR) opsin. These data establish that RPE cells are intrinsically sensitive to light. Finally, we show that in the dark, RGR-opsin inhibits lecithin:retinol acyltransferase and all-trans-retinyl ester hydrolase in vitro and that this inhibition is released upon exposure to light. The results of this study suggest that RGR-opsin mediates light-dependent translocation of all-trans-retinyl esters from a storage pool in lipid droplets to an "isomerase pool" in membranes of the endoplasmic reticulum. This translocation permits insoluble all-trans-retinyl esters to be utilized as substrate for the synthesis of a new visual chromophore.

Received for publication, February 19, 2008 , and in revised form, May 12, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant NEI R01-EY01584. This work was also supported by the Foundation Fighting Blindness. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Dolly Green Professor of Ophthalmology.

² Charles Kenneth Feldman and Jules and Doris Stein Research to Prevent Blindness Professor. To whom correspondence should be addressed. Tel.: 310-267-2673; E-mail: travis{at}jsei.ucla.edu.

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