Regulation of Isomerohydrolase Activity in the Visual Cycle

Winston, Anette; Rando, Robert R.

doi:10.1021/bi971908d

Cited by 87 publications

(86 citation statements)

References 45 publications

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“…The isomerization reaction is inhibited by its product, 11-cis-ROL (53,54). This inhibition is relieved by the specific binding of 11-cis-ROL to cellular retinal-binding protein (CRALBP) in RPE cells (55,56).…”

Section: Reduction Of All-trans-ral To All-trans-rolmentioning

confidence: 99%

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Diseases Caused by Defects in the Visual Cycle: Retinoids as Potential Therapeutic Agents

Travis

Golczak

Moise

et al. 2007

Annu. Rev. Pharmacol. Toxicol.

370

452

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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.

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Section: Reduction Of All-trans-ral To All-trans-rolmentioning

confidence: 99%

“…As discussed above, binding of 11-cis-ROL by CRALBP is required to avoid product-inhibition of the isomerase (53,54). In the absence of CRALBP, synthesis of 11-cis-ROL, and hence 11-cis-RAL chromophore, is greatly slowed.…”

Section: Retinitis Punctata Albescens Caused By Mutations In the Rlbpmentioning

confidence: 99%

Diseases Caused by Defects in the Visual Cycle: Retinoids as Potential Therapeutic Agents

Travis

Golczak

Moise

et al. 2007

Annu. Rev. Pharmacol. Toxicol.

370

452

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“…Chicken and Bovine RPE Microsomes-Most of the previous measurements of RPE65 isomerohydrolase activity were performed using bovine RPE microsomes (22,23). However, it is not known if the specific activity of RPE65 is the same in cone-dominant species.…”

Section: Comparison Of the Isomerohydrolase Activities Of Rpe65 Inmentioning

confidence: 99%

RPE65 from Cone-dominant Chicken Is a More Efficient Isomerohydrolase Compared with That from Rod-dominant Species

Moiseyev

Takahashi

Chen

et al. 2008

Journal of Biological Chemistry

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Cones recover their photosensitivity faster than rods after bleaching. It has been suggested that a higher rate regeneration of 11-cis-retinal, the chromophore for visual pigments, is required for cones to continuously function under bright light conditions. RPE65 is the isomerohydrolase catalyzing a key step in regeneration of 11-cis-retinal. The present study investigated whether RPE65 in a cone-dominant species is more efficient in its enzymatic activity than that from roddominant species. In vitro isomerohydrolase activity assay showed that isomerohydrolase activity in the chicken retinal pigment epithelium (RPE) was 11.7-fold higher than in the bovine RPE, after normalization by RPE65 protein levels. Similar to that of human and bovine, the isomerohydrolase activity in chicken RPE was blocked by two specific inhibitors of lecithin retinal acyltransferase, indicating that chicken RPE65 also uses all-trans-retinyl ester as the direct substrate. To exclude the possibility that the higher isomerohydrolase activity in the chicken RPE could arise from another unknown isomerohydrolase, we expressed chicken and human RPE65 using the adenovirus system in a stable cell line expressing lecithin retinal acyltransferase. Under the same conditions, isomerohydrolase activity of recombinant chicken RPE65 was 7.7-fold higher than that of recombinant human RPE65, after normalization by RPE65 levels. This study demonstrates that RPE65 from the cone-dominant chicken RPE possesses significantly higher specific retinol isomerohydrolase activity, when compared with RPE65 from rod-dominant species, consistent with the faster regeneration rates of visual pigments in cone-dominant retinas.Visual pigments of rods and cones consist of protein opsins and the chromophore, 11-cis-retinal covalently bound to opsins via a Schiff base (1). Upon light absorption, the 11-cis-retinal is photoisomerized to all-trans-retinal, which subsequently activates opsin and triggers the phototransduction cascade (1, 2). The 11-cis-retinal chromophore regenerates through a series of reactions of the retinoid visual cycle (3, 4). The visual cycle has been intensively studied in rod-dominant species such as bovine and mouse. The twocell (photoreceptor and RPE) 2 system of 11-cis-retinal recycling has been proposed for the visual cycle. After reduction of all-trans-retinal by retinol dehydrogenase, the generated all-trans-retinol is transported from the photoreceptor to the RPE and esterified to all-trans-retinyl esters by lecithin retinol acyltransferase (LRAT). The resulting all-trans-retinyl ester can either be stored in the RPE or directly converted to 11-cis-retinol by the isomerohydrolase, which was recently identified as the microsomal protein RPE65 (5-7). RPE65 has been shown to be an essential enzyme in the retinoid visual cycle for 11-cis-retinal regeneration (8). After oxidation of 11-cis-retinol by retinol dehydrogenase-5, the generated 11-cis-retinal is transported back to the photoreceptors to regenerate the visual pigments.It is known that cone...

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“…Finally, 11-cis-retinol is oxidized to 11-cis-retinal and shuttled back to the photoreceptor outer segment. The reactions in the RPE depend on cellular retinaldehyde-binding protein (CRALBP), which acts as a substrate carrier to chaperone retinaldehyde through an aqueous milieu (Winston and Rando, 1998;Stecher et al, 1999). Mice with an inactivated Cralbp gene exhibit impaired visual pigment regeneration.…”

Section: Introductionmentioning

confidence: 99%

Subfunctionalization of a Retinoid-Binding Protein Provides Evidence for Two Parallel Visual Cycles in the Cone-Dominant Zebrafish Retina

Fleisch

Schönthaler²,

Lintig³

2008

J. Neurosci.

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In vertebrates, the absorption of a photon results in an 11-cis to all-trans isomerization of the retinylidene chromophore of cone and rod visual pigments. To sustain vision, metabolic pathways (visual cycles) have evolved that recycle all-trans-retinal back to 11-cis-retinal. The canonical visual cycle takes place in photoreceptor cells and the adjacent retinal pigment epithelium (RPE). Biochemical analyses provided evidence for the existence of an additional cone-specific visual cycle involving Müller glia cells, but none of its molecular components has yet been identified. Here we took advantage of the zebrafish retina to investigate the role of the cellular retinaldehydebinding protein CRALBP in this process. We found that the zebrafish genome encodes two cralbp paralogs: cralbp a and cralbp b. These paralogs are differentially expressed in the retina. Cralbp a is exclusively expressed in the RPE, and Cralbp b is localized to Müller cells. We used an antisense morpholino approach to knock down each cralbp paralog. Analysis of 11-cis-retinal levels revealed that visual chromophore regeneration is diminished under both conditions. Visual performance, as assessed by electroretinography, revealed reduced light sensitivity in both Cralbp a-and Cralbp b-deficient larvae, but it was more pronounced in Cralbp b-deficient larvae. Cralbp b-deficient larvae also exhibited significant deficits in their visual behavior. Together, these data demonstrate that Cralbp expression in Müller cells is essential for cone vision, thereby providing evidence that both the canonical and the alternative visual cycle depend on the same type of retinoid-binding protein.

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Regulation of Isomerohydrolase Activity in the Visual Cycle

Cited by 87 publications

References 45 publications

Diseases Caused by Defects in the Visual Cycle: Retinoids as Potential Therapeutic Agents

Diseases Caused by Defects in the Visual Cycle: Retinoids as Potential Therapeutic Agents

RPE65 from Cone-dominant Chicken Is a More Efficient Isomerohydrolase Compared with That from Rod-dominant Species

Subfunctionalization of a Retinoid-Binding Protein Provides Evidence for Two Parallel Visual Cycles in the Cone-Dominant Zebrafish Retina

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