Rosalie K. Crouch
Storm Eye Institute, Medical University of South Carolina 167 Ashley Avenue, Charleston, South Carolina 29403 crouchrk@musc.edu Introduction
Introduction
The processing of visual information begins in the retina with the detection of light by photoreceptor cells. In humans, two specialized types of photoreceptors detect light under different conditions. Rod photoreceptors are highly sensitive and mediate vision in dim light, while cone photoreceptors function in bright light and mediate both high acuity and color vision. To detect light, both rods and cones exploit the unique properties of 11-cis retinal, a photosensitive derivative of vitamin A. The 11-cis retinal in photoreceptors is covalently bound to an opsin signaling protein to form a visual pigment molecule. In the presence of light, 11- cis retinal is isomerized to all-trans retinal, and the straightening of the polyene chain activates the opsin (Figure 1). While the formation of alltrans retinal is essential for activating photoreceptors and initiating vision, neither the opsin nor the all-trans retinal are sensitive to light, and new 11-cis retinal must be provided for photoreceptors to function continuously. Brief shortages of 11-cis retinal are an uncomfortable but common event. For example, the inability to see at night after passing an oncoming car's bright lights is partially due to the depletion of 11-cis retinal in rods. While vision recovers from transient shortages, prolonged 11-cis retinal deficits in conditions like vitamin A deficiency can eventually lead to more pronounced visual deficits. To generate enough 11-cis retinal for the normal function and survival of photoreceptors, alltrans retinal is converted back into 11-cis retinal through a series of enzymatic steps known as the visual cycle.

Gabriel H. Travis1, Marcin Golczak2, Alexander R. Moise2, and Krzysztof Palczewski2 1 Department of Ophthalmology, UCLA School of Medicine, Los Angeles, California 90095; email: travis@jsei.ucla.edu 2 Department of Pharmacology, Case School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106-4965; email: kxp65@case.edu
Abstract
Absorption of a photon by an opsin pigment causes isomerization of the chromophore from 11-cisretinaldehyde to all-trans-retinaldehyde. Regeneration of visual chromophore following light exposure is dependent on an enzyme pathway called the retinoid or visual cycle. Our understanding of this pathway has been greatly facilitated by the identification of disease-causing mutations in the genes coding for visual cycle enzymes. Defects in nearly every step of this pathway are responsible for human-inherited retinal dystrophies. These retinal dystrophies can be divided into two etiologic groups. One involves the impaired synthesis of visual chromophore. The second involves accumulation of cytotoxic products derived from all-trans-retinaldehyde. Gene therapy has been successfully used in animal models of these diseases to rescue the function of enzymes involved in chromophore regeneration, restoring vision. Dystrophies resulting from impaired chromophore synthesis can also be treated by supplementation with a chromophore analog. Dystrophies resulting from the accumulation of toxic pigments can be treated pharmacologically by inhibiting the visual cycle, or limiting the supply of vitamin A to the eyes. Recent progress in both areas provides hope that multiple inherited retinal diseases will soon be treated by pharmaceutical intervention.