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The Journal of Neuroscience, April 9, 2008, 28(15):4008-4014; doi:10.1523/JNEUROSCI.0317-08.2008

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Neurobiology of Disease
Trafficking of Membrane-Associated Proteins to Cone Photoreceptor Outer Segments Requires the Chromophore 11-cis-Retinal

Houbin Zhang,¹ Jie Fan,³ Sha Li,¹ Sukanya Karan,⁵ Baerbel Rohrer,³ Krzysztof Palczewski,⁴ Jeanne M. Frederick,¹ Rosalie K. Crouch,³ and Wolfgang Baehr^1,2,5

Departments of ¹Ophthalmology and ²Neurobiology and Anatomy, University of Utah Health Science Center, Salt Lake City, Utah 84132, ³Department of Ophthalmology, Medical University of South Carolina, Charleston, South Carolina 29425, ⁴Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106, and ⁵Department of Biology, University of Utah, Salt Lake City, Utah 84112

Correspondence should be addressed to Wolfgang Baehr, John A. Moran Eye Center, University of Utah Health Science Center, Salt Lake City, UT 84132. Email: wbaehr{at}hsc.utah.edu

Lecithin retinol acyl transferase (LRAT) and retinal pigment epithelium protein 65 (RPE65) are key enzymes of the retinoid cycle. In Lrat^–/– and Rpe65^–/– mice, models of human Leber congenital amaurosis, the retinoid cycle is disrupted and 11-cis-retinal, the chromophore of visual pigments, is not produced. The Lrat^–/– and Rpe65^–/– retina phenotype presents with rapid sectorial cone degeneration, and the visual pigments, S-opsin and M/L-opsin, fail to traffic to cone outer segments appropriately. In contrast, rod opsin traffics normally in mutant rods. Concomitantly, guanylate cyclase 1, cone T-subunit, cone phosphodiesterase 6' (PDE6'), and GRK1 (G-protein-coupled receptor kinase 1; opsin kinase) are not transported to Lrat^–/– and Rpe65^–/– cone outer segments. Aberrant localization of these membrane-associated proteins was evident at postnatal day 15, before the onset of ventral and central cone degeneration. Protein levels of cone T and cone PDE6' were reduced, whereas their transcript levels were unchanged, suggesting posttranslational degradation. In an Rpe65^–/–Rho^–/– double knock-out model, trafficking of cone pigments and membrane-associated cone phototransduction polypeptides to the outer segments proceeded normally after 11-cis-retinal administration. These results suggest that ventral and central cone opsins must be regenerated with 11-cis-retinal to permit transport to the outer segments. Furthermore, the presence of 11-cis-retinal is essential for proper transport of several membrane-associated cone phototransduction polypeptides in these cones.

Key words: cone visual pigments; LRAT (lecithin retinol acyl transferase); RPE65; retinoid isomerase; membrane protein trafficking; Leber congenital amaurosis

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Received Jan. 23, 2008; revised March 7, 2008; accepted March 12, 2008.

Correspondence should be addressed to Wolfgang Baehr, John A. Moran Eye Center, University of Utah Health Science Center, Salt Lake City, UT 84132. Email: wbaehr{at}hsc.utah.edu

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