Chemistry and Biology of the Initial Steps in Vision: The Friedenwald Lecture

Abstract

Visual transduction is the process in the eye whereby absorption of light in the retina is translated into electrical signals that ultimately reach the brain. The first challenge presented by visual transduction is to understand its molecular basis. We know that maintenance of vision is a continuous process requiring the activation and subsequent restoration of a vitamin A-derived chromophore through a series of chemical reactions catalyzed by enzymes in the retina and retinal pigment epithelium (RPE). Diverse biochemical approaches that identified key proteins and reactions were essential to achieve a mechanistic understanding of these visual processes. The three-dimensional arrangements of these enzymes' polypeptide chains provide invaluable insights into their mechanisms of action. A wealth of information has already been obtained by solving high-resolution crystal structures of both rhodopsin and the retinoid isomerase from pigment RPE (RPE65). Rhodopsin, which is activated by photoisomerization of its 11-cis-retinylidene chromophore, is a prototypical member of a large family of membrane-bound proteins called G protein-coupled receptors (GPCRs). RPE65 is a retinoid isomerase critical for regeneration of the chromophore. Electron microscopy (EM) and atomic force microscopy have provided insights into how certain proteins are assembled to form much larger structures such as rod photoreceptor cell outer segment membranes. A second challenge of visual transduction is to use this knowledge to devise therapeutic approaches that can prevent or reverse conditions leading to blindness. Imaging modalities like optical coherence tomography (OCT) and scanning laser ophthalmoscopy (SLO) applied to appropriate animal models as well as human retinal imaging have been employed to characterize blinding diseases, monitor their progression, and evaluate the success of therapeutic agents. Lately two-photon (2-PO) imaging, together with biochemical assays, are revealing functional aspects of vision at a new molecular level. These multidisciplinary approaches combined with suitable animal models and inbred mutant species can be especially helpful in translating provocative cell and tissue culture findings into therapeutic options for further development in animals and eventually in humans. A host of different approaches and techniques is required for substantial progress in understanding fundamental properties of the visual system.

Photocyclic behavior of rhodopsin induced by an atypical isomerization mechanism

“…rhodopsin | vision | GPCR | isomerization | chromophore R hodopsin (Rh) is the visual pigment found in rod outer segments of vertebrate and invertebrate photoreceptors that mediates the transformation of light into vision (1)(2)(3)(4)(5). By contrast, microbial Rhs mediate both the energy conversion and cell signaling required for cell survival (2,6,7).…”

How lateral inhibition and fast retinogeniculo-cortical oscillations create vision: A new hypothesis

“…cGMP-gated channels close [34], resulting in the biochemical change of all-trans retinal into 11-cis retinal. This biochemical change regenerates rhodopsin [34] through the retinoid visual cycle [29], returning the cell to a dark state [34].…”

“…Phototransduction converts light to electro-chemical signals at each disc through utilization of rhodopsin, along with other proteins and transmitters resulting in vision [29]. The first step in visual transduction is the phototransduction cascade which converts light into chemical signals [30].…”

“…Not only does it cover more than half of the surface of rod discs, rod cells need it in order to survive [29]. Once photons enter the photoreceptors, rhodopsin absorbs them, and they become photoisomerized and changed from the 11-cis to the all-trans configuration, all of which takes place in 10 À12 s [15].…”

Vision Science: Can Rhodopsin Cure Blindness?

“…How is the rhodopsin photocycle mediated in these animals? Normally the close apposition of rods and RPE is thought to be important for the chromophore photocycle [16]; is the RPE responsible for the recycling of chromophore in these degenerated animals as well? If so, will utility of this approach be limited in patients with RPE dysfunction such as in atrophic macular degeneration?…”