Abstract
All that we view of the world begins with an ultrafast cis to trans photoisomerization of the retinylidene chromophore associated with the visual pigments of rod and cone photoreceptors. The continual responsiveness of these photoreceptors is then sustained by regeneration processes that convert the trans-retinoid back to an 11-cis configuration. Recent biochemical and electrophysiological analyses of the retinal G-protein-coupled receptor (RGR) suggest that it could sustain the responsiveness of photoreceptor cells, particularly cones, even under bright light conditions. Thus, two mechanisms have evolved to accomplish the reisomerization: one involving the well-studied retinoid isomerase (RPE65) and a second photoisomerase reaction mediated by the RGR. Impairments to the pathways that transform all-trans-retinal back to 11-cis-retinal are associated with mild to severe forms of retinal dystrophy. Moreover, with age there also is a decline in the rate of chromophore regeneration. Both pharmacological and genetic approaches are being used to bypass visual cycle defects and consequently mitigate blinding diseases. Rapid progress in the use of genome editing also is paving the way for the treatment of disparate retinal diseases. In this review, we provide an update on visual cycle biochemistry and then discuss visual-cycle-related diseases and emerging therapeutics for these disorders. There is hope that these advances will be helpful in treating more complex diseases of the eye, including age-related macular degeneration (AMD).
Highlights
Photoreceptor cell hyperpolarization and a change in chemical signaling at the first visual synapses between photoreceptors and bipolar cells [2,3,4]
Rho serves as a prototypical GPCR whose mechanism of signaling remains the best studied of any member of the GPCR superfamily [4, 5, 177]
Recent findings demonstrate that cones rely on both continuous retinoid isomerase (RPE65) activity and an independent second source of 11-cis-retinal for regeneration of their visual pigments [14]
Summary
All that we view of the world begins with an ultrafast cis to trans photoisomerization of the retinylidene chromophore associated with the visual pigments of rod and cone photoreceptors. With age there is a decline in the rate of chromophore regeneration Both pharmacological and genetic approaches are being used to bypass visual cycle defects and mitigate blinding diseases. Visual pigments contain a covalently bound 11-cis-retinal chromophore that undergoes cis–trans isomerization upon absorption of visible light [1] (Movie S1) This photoswitch enables the visual opsin to trigger a G protein signaling pathway that leads to. Visual cycle protein mutations produce blindness within the first or second decade of life [9], which has motivated studies to develop therapeutics for such conditions These include pharmacological agents that bypass the metabolic blockade in 11-cis-retinal synthesis [10, 11] and targeted genetic approaches involving gene augmentation or mutation correction using CRISPR/Cas or related technologies [12]. Where appropriate we cite other more specialized review articles, which deal with unique aspects of the visual cycle
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