Rapid restoration of visual pigment and function with oral retinoid in a mouse model of childhood blindness

Hooser, J. Preston Van; Alemán, Tomás S.; He, Yu Guang; Cideciyan, Artur V.; Kuksa, Vladimir; Pittler, Steven J.; Stone, Edwin M.; Jacobson, Samuel G.; Palczewski, Krzysztof

doi:10.1073/pnas.150236297

Cited by 232 publications

(254 citation statements)

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“…Van Hooser et al (5) reported that the small a-waves that could be recorded in the Rpe65 Ϫ/Ϫ mice under bright light conditions were characterized by low photoreceptor sensitivity with no obvious change in gain of the photoreceptor transduction cascade or temporal characteristics. In a follow-up study using single-cell recordings (6), they demonstrated that Rpe65 Ϫ/Ϫ rods have responses greatly reduced in sensitivity and amplitude, whereas kinetics were similar to, but slightly faster than, WT kinetics.…”

Section: Discussionmentioning

confidence: 99%

“…The photoreceptors of Rpe65 Ϫ/Ϫ mice are almost completely depleted of 11-cis-retinal, the native ligand of cone and rod opsins, resulting in minimal levels of rhodopsin and the deterioration of their photosensitivity (4). Photoreceptor function has been shown to be partially restored by supplying exogenous ligand (5,6). Thus, the Rpe65 Ϫ/Ϫ mouse is an excellent model in which to study the two key factors that control the activity of rhodopsin, the supply of the ligand (7,8) and the level of rhodopsin/opsin phosphorylation.…”

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confidence: 99%

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11-cis-Retinal Reduces Constitutive Opsin Phosphorylation and Improves Quantum Catch in Retinoid-deficient Mouse Rod Photoreceptors

Ablonczy

Crouch

Goletz

et al. 2002

Journal of Biological Chemistry

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Rpe65 ؊/؊ mice produce minimal amounts of 11-cis-retinal, the ligand necessary for the formation of photosensitive visual pigments. Therefore, the apoprotein opsin in these animals has not been exposed to its normal ligand. The Rpe65 ؊/؊ mice contain less than 0.1% of wild type levels of rhodopsin. Mass spectrometric analysis of opsin from Rpe65 ؊/؊ mice revealed unusually high levels of phosphorylation in dark-adapted mice but no other structural alterations. Single flash and flicker electroretinograms (ERGs) from 1-month-old animals showed trace rod function but no cone response. B-wave kinetics of the single-flash ERG are comparable with those of dark-adapted wild type mice containing a full compliment of rhodopsin. Application (intraperitoneal injection) of 11-cis-retinal to Rpe65 ؊/؊ mice increased the rod ERG signal, increased levels of rhodopsin, and decreased opsin phosphorylation. Therefore, exogenous 11-cis-retinal improves photoreceptor function by regenerating rhodopsin and removes constitutive opsin phosphorylation. Our results indicate that opsin, which has not been exposed to 11-cis-retinal, does not generate the activity generally associated with the bleached apoprotein.RPE65 is a major protein in the retinal pigment epithelium (RPE) 1 (1) and has also been identified in cone photoreceptors (2, 3). The photoreceptors of Rpe65 Ϫ/Ϫ mice are almost completely depleted of 11-cis-retinal, the native ligand of cone and rod opsins, resulting in minimal levels of rhodopsin and the deterioration of their photosensitivity (4). Photoreceptor function has been shown to be partially restored by supplying exogenous ligand (5, 6). Thus, the Rpe65 Ϫ/Ϫ mouse is an excellent model in which to study the two key factors that control the activity of rhodopsin, the supply of the ligand (7, 8) and the level of rhodopsin/opsin phosphorylation. Therefore, we have analyzed opsin phosphorylation levels of Rpe65 Ϫ/Ϫ mice and correlated those levels with electroretinogram (ERG) responses and rhodopsin levels in the absence and presence of exogenous 11-cis-retinal.Retinal function is controlled by the availability of 11-cisretinal, which can be affected by the absence or dysfunction of any number of participants in the retinal metabolic pathway (e.g. Refs. 9 and 10). RPE65 is essential for production of 11-cis-retinoids (4). RPE65 mutations in humans result in congenital retinal dystrophies ranging from night blindness to loss of vision (11). Although night blindness would suggest loss of rod rather than cone function, the ERG retained in Rpe65 Ϫ/Ϫ mice appears to originate from rod photoreceptors (12).A second key factor that controls visual sensitivity is opsin/ rhodopsin phosphorylation. The C terminus of activated rhodopsin is multiply phosphorylated by rhodopsin kinase (G protein-coupled receptor kinase 1) (13) in vivo (14,15), and this multiple phosphorylation has been shown to be necessary for the rapid return of sensitivity (16). In moderate light levels, it has been proposed that opsin dephosphorylation and its regen...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

11-cis-Retinal Reduces Constitutive Opsin Phosphorylation and Improves Quantum Catch in Retinoid-deficient Mouse Rod Photoreceptors

Ablonczy

Crouch

Goletz

et al. 2002

Journal of Biological Chemistry

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“…As in vitamin A-deprived rats and humans, the sensitivity can be rapidly restored by treatment with supplemental chromophore. (42)(43)(44)(45) Rods in Rpe65 À/À mice behave as if in the presence of a continuous background light. (46) Light responses are only a fraction of their normal amplitude and show an accelerated turn-off, characteristic of light-adapted photoreceptors (see Ref.…”

Section: Continuous Light Kills By Activating Transductionmentioning

confidence: 99%

Why photoreceptors die (and why they don't)

Fain

2006

BioEssays

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Light can kill the photoreceptors of the eye, not only very bright direct sunlight, but more moderate illumination if the light is present continuously. Recent experiments show that rod apoptosis can be triggered by strong and constant activation of transduction, and that death can be prevented if transduction is inhibited even though the eye is illuminated. Vitamin A deficiency and genetically inherited diseases, such as some forms of retinitis pigmentosa and Leber congenital amaurosis, appear to kill like this: transduction is activated at a high rate and continuously, and this causes the rods to die. Why does transduction kill? Our best guess is that continuous activation produces a prolonged lowering of the Ca2+ concentration, which is also thought to kill neurons in tissue culture and during the development of the nervous system. To prevent death in constant light, rods have evolved protective mechanisms including modulation of channels and ion transport to keep the Ca2+ from going too low. Prolonged light exposure also causes migration of transduction proteins from one part of the cell to another and a reversible shortening of the rod outer segments, the part of the cell that contains the pigment rhodopsin. All of these mechanisms are at work in the normal eye to reduce transduction and prevent the Ca2+ concentration from dropping too low for too long a time. That most of us retain our vision our entire lives is a testament to their effectiveness. BioEssays 28: 344–354, 2006. © 2006 Wiley Periodicals, Inc.

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“…These retinols are stored in the form of retinyl esters before use. Because 9-cis-retinal is more stable than 9-cis-retinol, an alternative pathway in the production of 9-cis-isomers is the isomerization of all-trans-retinol to 9-cis-retinol (43). Although the equilibrium is shifted toward the all-trans-isomers (5), small amounts of 9-cis-retinal would be trapped as it is formed and further oxidized by aldehyde dehydrogenases (44).…”

Section: Involvement Of Rdh11-14 In Retinoid Transformation and All-tmentioning

confidence: 99%

Dual-substrate Specificity Short Chain Retinol Dehydrogenases from the Vertebrate Retina

Haeseleer¹,

Jang²,

Imanishi³

et al. 2002

Journal of Biological Chemistry

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Retinoids are chromophores involved in vision, transcriptional regulation, and cellular differentiation. Members of the short chain alcohol dehydrogenase/reductase superfamily catalyze the transformation of retinol to retinal. Here, we describe the identification and properties of three enzymes from a novel subfamily of four retinol dehydrogenases (RDH11-14) that display dualsubstrate specificity, uniquely metabolizing all-trans-and cis-retinols with C 15 pro-R specificity. RDH11-14 could be involved in the first step of all-trans-and 9-cis-retinoic acid production in many tissues. RDH11-14 fill the gap in our understanding of 11-cis-retinal and all-trans-retinal transformations in photoreceptor (RDH12) and retinal pigment epithelial cells (RDH11). The dualsubstrate specificity of RDH11 explains the minor phenotype associated with mutations in 11-cisretinol dehydrogenase (RDH5) causing fundus albipunctatus in humans and engineered mice lacking RDH5. Furthermore, photoreceptor RDH12 could be involved in the production of 11-cis-retinal from 11-cis-retinol during regeneration of the cone visual pigments. These newly identified enzymes add new elements to important retinoid metabolic pathways that have not been explained by previous genetic and biochemical studies.Retinoids are indispensable light-sensitive elements of vision and also serve as essential modulators of cellular differentiation and proliferation in diverse cell types, including those comprising the epithelium and immune system. Retinoids modulate the growth of both normal and malignant cells through their binding to retinoid receptors. All-trans-retinoic acid signals through specific interactions with the nuclear retinoic acid receptors, whereas its isomer, 9-cis-retinoic acid, is a high affinity ligand of retinoic acid receptors and retinoid X receptors. In the retina, light-dependent photoisomerization of 11-cis-retinylidene to the all-transretinylidene moiety of rod and cone photoreceptors is a key reaction that triggers visual * This research was supported by National Institutes of Health Grants EY08061, CA75173, and DK59125, a grant from Research to Prevent Blindness, Inc. (to the Department of Ophthalmology, University of Washington), and by the E. K. Bishop Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. S The on-line version of this article (available at http://www.jbc.org) contains Supplemental Figs. 1 and 2 and Tables 1-3. § These authors contributed equally to this work. § § Recipient of a Research to Prevent Blindness Senior Investigator Award. To whom correspondence should be addressed: Dept. of Ophthalmology, University of Washington, Seattle,; E-mail: palczews@u.washington.edu. Transformations of retinoids occur mostly through enzymatic or photochemical reactions, although they readily isomerize non-enzymatically to thermodynamic equilibriu...

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Rapid restoration of visual pigment and function with oral retinoid in a mouse model of childhood blindness

Cited by 232 publications

References 44 publications

11-cis-Retinal Reduces Constitutive Opsin Phosphorylation and Improves Quantum Catch in Retinoid-deficient Mouse Rod Photoreceptors

11-cis-Retinal Reduces Constitutive Opsin Phosphorylation and Improves Quantum Catch in Retinoid-deficient Mouse Rod Photoreceptors

Why photoreceptors die (and why they don't)

Dual-substrate Specificity Short Chain Retinol Dehydrogenases from the Vertebrate Retina

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