ATP-binding cassette transporter ABCA4 and chemical isomerization protect photoreceptor cells from the toxic accumulation of excess 11-
            <i>cis</i>
            -retinal

Quazi, Faraz; Molday, Robert S.

doi:10.1073/pnas.1400780111

Cited by 113 publications

(109 citation statements)

References 39 publications

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“…Our findings in dark-reared mice and the data of Boyer et al support the notion that bisretinoid can form from 11-cis-retinal in vivo (40). The relative contributions of 11-cis-and all-trans-retinal to bisretinoid formation under lighted conditions are not known, but in both cases, only a small portion of retinoid escapes the visual cycle to form bisretinoid.…”

Section: Discussionsupporting

confidence: 88%

“…The relative contributions of 11-cis-and all-trans-retinal to bisretinoid formation under lighted conditions are not known, but in both cases, only a small portion of retinoid escapes the visual cycle to form bisretinoid. With respect to bisretinoid formation in Abca4 −/− mice, it is significant to note that ABCA4 can transport both 11-cisretinal and all-trans-retinal as a reversible Schiff base with PE (40).…”

Section: Discussionmentioning

confidence: 99%

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Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration

Ueda

Zhao

Kim

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

111

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Adducts of retinaldehyde (bisretinoids) form nonenzymatically in photoreceptor cells and accumulate in retinal pigment epithelial (RPE) cells as lipofuscin; these fluorophores are implicated in the pathogenesis of inherited and age-related macular degeneration (AMD). Here we demonstrate that bisretinoid photodegradation is ongoing in the eye. High-performance liquid chromatography (HPLC) analysis of eyes of dark-reared and cyclic light-reared wild-type mice, together with comparisons of pigmented versus albino mice, revealed a relationship between intraocular light and reduced levels of the bisretinoids A2E and A2-glycero-phosphoethanolamine (A2-GPE). Analysis of the bisretinoids A2E, A2-GPE, A2-dihydropyridinephosphatidylethanolamine (A2-DHP-PE), and all-trans-retinal dimerphosphatidylethanolamine (all-trans-retinal dimer-PE) also decreases in albino Abca4 −/− mice reared in cyclic light compared with darkness. In albino Abca4 −/− mice receiving a diet supplemented with the antioxidant vitamin E, higher levels of RPE bisretinoid were evidenced by HPLC analysis and quantitation of fundus autofluorescence; this effect is consistent with photooxidative processes known to precede bisretinoid degradation. Amelioration of outer nuclear layer thinning indicated that vitamin E treatment protected photoreceptor cells. Conversely, in-cage exposure to short-wavelength light resulted in reduced fundus autofluorescence, decreased HPLC-quantified A2E, outer nuclear layer thinning, and increased methylglyoxal (MG)-adducted protein. MG was also released upon bisretinoid photodegradation in cells. We suggest that the lower levels of these diretinal adducts in cyclic lightreared and albino mice reflect photodegradative loss of bisretinoid. These mechanisms may underlie associations among AMD risk, oxidative mechanisms, and lifetime light exposure.bisretinoid | visual cycle | retina | retinal pigment epithelium | macular degeneration

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration

Ueda

Zhao

Kim

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

111

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“…Whereas it was originally thought that this reaction required all- trans -retinal, released from rhodopsin after light exposure, 72–74 recent reports suggest instead that 11- cis -retinal is the critical molecule in this pathway. 75,76 Thus, N -11- cis -retinylidene-PE ( N - cis -R-PE) is formed from 11- cis -retinal that is delivered to the discs by the visual cycle, or after catabolism of rhodopsin. N - cis -R-PE isomerizes to N -all- trans -R-PE, 76 before addition of a second retinaldehyde converts NRPE irreversibly to A2-PE in the disc; A2-PE is eventually hydrolyzed to A2E after discs are phagocytosed by the RPE.…”

Section: Biological Function Of Rhodopsin-mediated Lipid Scrambling Imentioning

confidence: 99%

“…75,76 Thus, N -11- cis -retinylidene-PE ( N - cis -R-PE) is formed from 11- cis -retinal that is delivered to the discs by the visual cycle, or after catabolism of rhodopsin. N - cis -R-PE isomerizes to N -all- trans -R-PE, 76 before addition of a second retinaldehyde converts NRPE irreversibly to A2-PE in the disc; A2-PE is eventually hydrolyzed to A2E after discs are phagocytosed by the RPE. ABCA4 is predicted to play a key role in minimizing A2-PE production by flipping NRPE from the lumenal side to the cytoplasmic face of discs before it can be converted to A2-PE.…”

Section: Biological Function Of Rhodopsin-mediated Lipid Scrambling Imentioning

confidence: 99%

Phospholipid scrambling by rhodopsin

Ernst

Menon

2015

Photochem Photobiol Sci

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Rhodopsin has been intensively characterized in its role as a visual pigment and G protein-coupled receptor responsible for dim-light vision. We recently discovered that it also functions as an ATP-independent phospholipid scramblase: when reconstituted into large unilamellar vesicles, rhodopsin accelerates the normally sluggish transbilayer translocation of common phospholipids by more than 1000-fold, to rates in excess of 10,000 phospholipids transported per rhodopsin per second. Here we summarize the work leading to this discovery and speculate on the mechanism by which rhodopsin scrambles phospholipids. We also present a hypothesis that rhodopsin’s scramblase activity is necessary for the function of the ABC transporter ABCA4 that is responsible for mitigating the toxic accumulation of 11-cis-retinal and bis-retinoids in the retina.

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“…Bis -retinoids are thought to originate in the outer segments of the photoreceptor cells of the retina from reactions of the 11- cis and all- trans isomers of retinal 7–11 . Both of these isomers are necessary intermediates of the process of light detection that takes place in the outer segments of the photoreceptor cells.…”

Section: Introductionmentioning

confidence: 99%

Determination of N-retinylidene-N-retinylethanolamine (A2E) levels in central and peripheral areas of human retinal pigment epithelium

Adler

Boyer

Anderson

et al. 2015

Photochem Photobiol Sci

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SUMMARY The bis-retinoid N-retinylidene-N-retinylethanolamine (A2E) is one of the major components of lipofuscin, a fluorescent material that accumulates with age in the lysosomes of the retinal pigment epithelium (RPE) of the human eye. Lipofuscin, as well as A2E, exhibit a range of cytotoxic properties, which are thought to contribute to the pathogenesis of degenerative diseases of the retina such as Age-related Macular Degeneration. Consistent with such a pathogenic role, high levels of lipofuscin fluorescence are found in the central area of the human RPE, and decline toward the periphery. Recent reports have however suggested a surprising incongruence between the distributions of lipofuscin and A2E in the human RPE, with A2E levels being lowest in the central area and increasing toward the periphery. To appraise such a possibility, we have quantified the levels of A2E in the central and peripheral RPE areas of 10 eyes from 6 human donors (ages 75–91 years) with HPLC and UV/VIS spectroscopy. The levels of A2E in the central area were on average 3–6 times lower than in peripheral areas of the same eye. Furthermore, continuous accumulation of selected ions (CASI) imaging mass spectrometry showed the presence of A2E in the central RPE, and at lower intensities than in the periphery. We have therefore corroborated that in human RPE the levels of A2E are lower in the central area compared to the periphery. We conclude that the levels of A2E cannot by themselves provide an explanation for the higher lipofuscin fluorescence found in the central area of the human RPE.

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ATP-binding cassette transporter ABCA4 and chemical isomerization protect photoreceptor cells from the toxic accumulation of excess 11- cis -retinal

Cited by 113 publications

References 39 publications

Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration

Photodegradation of retinal bisretinoids in mouse models and implications for macular degeneration

Phospholipid scrambling by rhodopsin

Determination of N-retinylidene-N-retinylethanolamine (A2E) levels in central and peripheral areas of human retinal pigment epithelium

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