Dr. Baehr Published in Prestigious Journal of Neuroscience
In April 2008, the Journal of Neuroscience published the article "Trafficking of Membrane-associated Proteins to Cone Photoreceptor Outer Segments Requires the Chromophore 11-cis-Retinal" (JN-RM-0317-08.R1), in collaboration with a group of the Medical University of South Carolina. The research described in this paper determines mechanisms of cone degeneration in mouse models in which two key retinoid cycle genes were deleted.
Photon absorption by photosensitive visual pigments in rod and cone photoreceptors initiates vision. Visual pigments are G protein-coupled receptors using as their ligand 11-cis-retinal, which isomerizes to the all-trans form with light. Regeneration of 11-cis-retinal in the retinoid cycle is essential for maintaining normal visual function.
In the absence of LRAT and RPE65, 11-cis-retinal cannot be produced. In the Lrat-/- mouse, only trace amounts of all-trans-retinyl esters were detected. In contrast, in the Rpe65-/- mouse, retinyl esters accumulate. The Baehr lab showed that as a consequence of absence of chromophore, cone opsins and polypeptides of the cone phototransduction cascade failed to transport to the cone outer segments, vision cannot be initiated, and moreover, cone photoreceptors rapidly degenerated. A key discovery was that early and repeated intraperitoneal administration of exogenous 11-cis-retinal to mutant mice much delayed cone degeneration and prevented these mislocalizations. The data suggest that 11-cis-retinal binding to cone opsin is required for correct targeting and trafficking.
Figure 1. The retinoid cycle works like this: After photobleaching, all-trans-retinal separates from rhodopsin and cone opsins, and is reduced to all-trans-retinol (Vitamin A). All-trans-retinol, in turn, is exported to the retinal pigment epithelium (RPE) where it is converted into retinyl esters by lecithin retinol acyltransferase (LRAT). All-trans retinyl esters are the substrate for RPE65, recently identified as the retinoid isomerase that generates 11-cis-retinol. After oxidation to 11-cis-retinal, the chromophore is exported back to the photoreceptors for the regeneration of functional pigments. Correct functioning of the retinoid cycle is of fundamental importance in mammalian vision. Defects in retinoid cycle genes cause severe retina dystrophies, including macular degeneration, Leber congenital amaurosis, and retinitis pigmentosa (see Figure).