The Experts below are selected from a list of 303 Experts worldwide ranked by ideXlab platform
Yiannis Koutalos - One of the best experts on this subject based on the ideXlab platform.
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Interphotoreceptor retinoid-binding protein removes All-Trans-Retinol and retinal from rod outer segments, preventing lipofuscin precursor formation.
Journal of Biological Chemistry, 2017Co-Authors: Chunhe Chen, Leopold Adler, Patrice Goletz, Federico Gonzalez-fernandez, Debra A. Thompson, Yiannis KoutalosAbstract:: Interphotoreceptor retinoid-binding protein (IRBP) is a specialized lipophilic carrier that binds the all-trans and 11-cis isomers of retinal and retinol, and this facilitates their transport between photoreceptors and cells in the retina. One of these retinoids, all-trans-retinal, is released in the rod outer segment by photoactivated rhodopsin after light excitation. Following its release, all-trans-retinal is reduced by the retinol dehydrogenase RDH8 to All-Trans-Retinol in an NADPH-dependent reaction. However, all-trans-retinal can also react with outer segment components, sometimes forming lipofuscin precursors, which after conversion to lipofuscin accumulate in the lysosomes of the retinal pigment epithelium and display cytotoxic effects. Here, we have imaged the fluorescence of All-Trans-Retinol, all-trans-retinal, and lipofuscin precursors in real time in single isolated mouse rod photoreceptors. We found that IRBP removes All-Trans-Retinol from individual rod photoreceptors in a concentration-dependent manner. The rate constant for retinol removal increased linearly with IRBP concentration with a slope of 0.012 min-1 μm-1 IRBP also removed all-trans-retinal, but with much less efficacy, indicating that the reduction of retinal to retinol promotes faster clearance of the photoisomerized rhodopsin chromophore. The presence of physiological IRBP concentrations in the extracellular medium resulted in lower levels of all-trans-retinal and retinol in rod outer segments following light exposure. It also prevented light-induced lipofuscin precursor formation, but it did not remove precursors that were already present. These findings reveal an important and previously unappreciated role of IRBP in protecting the photoreceptor cells against the cytotoxic effects of accumulated all-trans-retinal.
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All‐Trans Retinal Mediates Light‐Induced Oxidation in Single Living Rod Photoreceptors†
Photochemistry and Photobiology, 2012Co-Authors: Kosuke Masutomi, Kei Nakatani, Chunhe Chen, Yiannis KoutalosAbstract:All-trans retinal is a potent photosensitizer that is released in photoreceptor outer segments by the photoactivated visual pigment following the detection of light. Photoreceptor outer segments also contain high concentrations of polyunsaturated fatty acids, and are thus particularly susceptible to oxidative damage such as that initiated by light via a photosensitizer. Upon its release, all-trans retinal is reduced within the outer segment to all-trans retinol, through a reaction requiring metabolic input in the form of NADPH. The phototoxic potential of physiologically generated all-trans retinal was examined in single living rod photoreceptors obtained from frog (Rana pipiens) retinas. Light-induced oxidation was measured with fluorescence imaging using an oxidation-sensitive indicator dye from the shift in fluorescence between the intact and oxidized forms. Light-induced oxidation was highest in metabolically compromised rod outer segments following photoactivation of the visual pigment rhodopsin, and after a time interval, sufficiently long to ensure the release of all-trans retinal. Furthermore, light-induced oxidation increased with the concentration of exogenously added all-trans retinal. The results show that the all-trans retinal generated during the detection of light can mediate light-induced oxidation. Its removal through reduction to all-trans retinol protects photoreceptor outer segments against light-induced oxidative damage.
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2-Hydroxypropyl-β-Cyclodextrin Removes All-Trans Retinol from Frog Rod Photoreceptors in a Concentration-Dependent Manner
Journal of Ocular Pharmacology and Therapeutics, 2010Co-Authors: Daniel Johnson, Chunhe Chen, Yiannis KoutalosAbstract:Abstract Purpose: To determine whether a nonprotein lipophilic carrier, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), can remove all-trans retinol from rod photoreceptor outer segments. All-trans retinol is generated in rod outer segments after light exposure. It is highly insoluble, and its efficient transport across extra- and intracellular aqueous space requires specialized carriers. Methods: Experiments were carried out with isolated frog rod photoreceptor cells. The removal of all-trans retinol by different concentrations of this carrier was measured by imaging its fluorescence in single-rod photoreceptors. Results: HP-β-CD concentrations >0.3 mM significantly increased the rate of all-trans retinol removal. The rate of removal increased linearly with carrier concentration, with a slope of 0.0058 min−1/mM. Conclusions: The effectiveness of HP-β-CD shows that a specialized interaction with the cell membrane is not necessary for the efficient transfer of all-trans retinol between the cell membrane and the ...
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Rapid formation of all-trans retinol after bleaching in frog and mouse rod photoreceptor outer segments
Photochemical and Photobiological Sciences, 2010Co-Authors: Chunhe Chen, Yiannis KoutalosAbstract:All-trans retinol is formed in the outer segments of vertebrate rod photoreceptors from the reduction of the all-trans retinal released by photoactivated rhodopsin. The reduction requires NADPH and is therefore dependent on metabolic input. In metabolically intact photoreceptors, a large increase in rod outer segment fluorescence, attributed to the fluorescence of all-trans retinol, follows rhodopsin photoactivation. The fluorescence increase is biphasic, including a rapid and a slow component. In metabolically compromised cells, there is a much smaller fluorescence increase following rhodopsin photoactivation, but it too contains a rapid component. We have measured the fluorescence signal in single living frog and mouse rod photoreceptors, and have characterized its dependence on the wavelengths of light selected for excitation and for collecting emission. We find that in metabolically intact cells, the excitation and emission properties of both the rapid and slow components of the fluorescence signal are in close agreement with those of all-trans retinol fluorescence. In metabolically compromised cells, however, the signal can only partially be due to all-trans retinol, and most of it is consistent with all-trans retinal. The results suggest that in the outer segments of living rod photoreceptors there is rapid release of all-trans retinal, which in metabolically intact cells is accompanied by rapid conversion to all-trans retinol.
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Microfluorometric measurement of the formation of All-Trans-Retinol in the outer segments of single isolated vertebrate photoreceptors.
Methods of Molecular Biology, 2010Co-Authors: Yiannis Koutalos, M. Carter CornwallAbstract:: The first step in the detection of light by vertebrate photoreceptors is the photoisomerization of the retinyl chromophore of their visual pigment from 11-cis to the all-trans configuration. This initial reaction leads not only to an activated form of the visual pigment, meta II, that initiates reactions of the visual transduction cascade but also to the photochemical destruction of the visual pigment. By a series of reactions termed the visual cycle, native visual pigment is regenerated. These coordinated reactions take place in the photoreceptors themselves as well as the adjacent pigment epithelium and Muller cells. The critical initial steps in the visual cycle are the release of all-trans-retinal from the photoactivated pigment and its reduction to All-Trans-Retinol. The goal of this monograph is to describe methods of fluorescence imaging that allow the measurement of changes in the concentration of All-Trans-Retinol as it is reduced from all-trans-retinal in isolated intact salamander and mouse photoreceptors. The kinetics of All-Trans-Retinol formation depend on cellular factors that include the visual pigment and photoreceptor cell type, as well as the cytoarchitecture of outer segments. In general, All-Trans-Retinol forms much faster in cone cells than in rods.
Krzysztof Palczewski - One of the best experts on this subject based on the ideXlab platform.
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Noninvasive two-photon microscopy imaging of mouse retina and retinal pigment epithelium through the pupil of the eye
Nature Medicine, 2014Co-Authors: Grazyna Palczewska, Marcin Golczak, Zhiqian Dong, Jennifer J Hunter, David R Williams, Nathan S Alexander, Krzysztof PalczewskiAbstract:Repetitive dynamic two-photon imaging of retinoid cycle fluorophores and subcellular details of their location within the retinal pigment epithelium in intact eyes of live mice. Two-photon excitation microscopy can image retinal molecular processes in vivo . Intrinsically fluorescent retinyl esters in subcellular structures called retinosomes are an integral part of the visual chromophore regeneration pathway. Fluorescent condensation products of all- trans -retinal accumulate in the eye with age and are also associated with age-related macular degeneration (AMD). Here, we report repetitive, dynamic imaging of these compounds in live mice through the pupil of the eye. By leveraging advanced adaptive optics, we developed a data acquisition algorithm that permitted the identification of retinosomes and condensation products in the retinal pigment epithelium by their characteristic localization, spectral properties and absence in genetically modified or drug-treated mice. This imaging approach has the potential to detect early molecular changes in retinoid metabolism that trigger light- and AMD-induced retinal defects and to assess the effectiveness of treatments for these conditions.
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Chemistry of the retinoid (visual) cycle
Chemical Reviews, 2014Co-Authors: Philip D Kiser, Marcin Golczak, Krzysztof PalczewskiAbstract:The involvement of retinoids in supporting vision via light-sensitive rod and cone photoreceptor cells in the retina is studied. Retinol travels in the circulation bound to RBP. In turn, RBP complexes with a transthyretin (TTR) tetramer, which prevents filtration of RBP across the glomeruli of the kidney. Holo-RBP can dissociate from the TTR tetramer and bind to the retinol membrane transporter, STRA6. All-Trans-Retinol is picked up on the cytoplasmic side of STRA6 by CRBP, which shuttles the retinoid to the ER of the RPE (retinal pigment epithelium). There it is esterified by LRAT (Lecithin/Retinol Acyl Transferase) to form all-transretinyl-esters, which are either used as substrates for visual chromophore production or stored in lipid bodies known as retinosomes, atROL, All-Trans-Retinol; atRE, all-trans-retinyl ester.
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melanopsin is highly resistant to light and chemical bleaching in vivo
Journal of Biological Chemistry, 2012Co-Authors: Timothy J Sexton, Marcin Golczak, Krzysztof Palczewski, Russell N Van GelderAbstract:Abstract Melanopsin is the photopigment of mammalian intrinsically photosensitive retinal ganglion cells (ipRGCs), where it contributes to light entrainment of circadian rhythms, and to the pupillary light response. Previous work has shown the melanopsin photocycle is independent of that used by rhodopsin (1). Here we determined the ability of apo-melanopsin, formed by ex vivo ultraviolet (UV) light bleaching, to use selected chromophores. We found that 9-cis-retinal, but not all-trans-retinal or 9-cis-retinol, is able to restore light-dependent ipRGC activity after bleaching. Melanopsin was highly resistant to both visible-spectrum photic bleaching and chemical bleaching with hydroxylamine under conditions that fully bleach rod and cone photoreceptor cells. These results suggest that the melanopsin photocycle can function independently of both rod and cone photocycles, and that apo-melanopsin has a strong preference for binding cis-retinal to generate functional pigment. The data support a model in which retinal is continuously covalently bound to melanopsin and may function through a reversible, bistable mechanism.
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metabolic basis of visual cycle inhibition by retinoid and nonretinoid compounds in the vertebrate retina
Journal of Biological Chemistry, 2008Co-Authors: Marcin Golczak, Akiko Maeda, Grzegorz Bereta, Tadao Maeda, Philip D Kiser, Silke Hunzelmann, Johannes Von Lintig, William S Blaner, Krzysztof PalczewskiAbstract:In vertebrate retinal photoreceptors, the absorption of light by rhodopsin leads to photoisomerization of 11-cis-retinal to its all-trans isomer. To sustain vision, a metabolic system evolved that recycles all-trans-retinal back to 11-cis-retinal. The importance of this visual (retinoid) cycle is underscored by the fact that mutations in genes encoding visual cycle components induce a wide spectrum of diseases characterized by abnormal levels of specific retinoid cycle intermediates. In addition, intense illumination can produce retinoid cycle by-products that are toxic to the retina. Thus, inhibition of the retinoid cycle has therapeutic potential in physiological and pathological states. Four classes of inhibitors that include retinoid and nonretinoid compounds have been identified. We investigated the modes of action of these inhibitors by using purified visual cycle components and in vivo systems. We report that retinylamine was the most potent and specific inhibitor of the retinoid cycle among the tested compounds and that it targets the retinoid isomerase, RPE65. Hydrophobic primary amines like farnesylamine also showed inhibitory potency but a short duration of action, probably due to rapid metabolism. These compounds also are reactive nucleophiles with potentially high cellular toxicity. We also evaluated the role of a specific protein-mediated mechanism on retinoid cycle inhibitor uptake by the eye. Our results show that retinylamine is transported to and taken up by the eye by retinol-binding protein-independent and retinoic acid-responsive gene product 6-independent mechanisms. Finally, we provide evidence for a crucial role of lecithin: retinol acyltransferase activity in mediating tissue specific absorption and long lasting therapeutic effects of retinoid-based visual cycle inhibitors.
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Isomerization of All-Trans-Retinol to cis-retinols in bovine retinal pigment epithelial cells: dependence on the specificity of retinoid-binding proteins.
Biochemistry, 2000Co-Authors: Joshua K. Mcbee, Vladimir A. Kuksa, Rosana Alvarez, A. R. De Lera, Oleg V. Prezhdo, Franc¸oise Haeseleer, Izabela Sokal, Krzysztof PalczewskiAbstract:In the retinal rod and cone photoreceptors, light photoactivates rhodopsin or cone visual pigments by converting 11-cis-retinal to all-trans-retinal, the process that ultimately results in phototransduction and visual sensation. The production of 11-cis-retinal in adjacent retinal pigment epithelial (RPE) cells is a fundamental process that allows regeneration of the vertebrate visual system. Here, we present evidence that All-Trans-Retinol is unstable in the presence of H+ and rearranges to anhydroretinol through a carbocation intermediate, which can be trapped by alcohols to form retro-retinyl ethers. This ability of All-Trans-Retinol to form a carbocation could be relevant for isomerization. The calculated activation energy of isomerization of all-trans-retinyl carbocation to the 11-cis-isomer was only ∼18 kcal/mol, as compared to ∼36 kcal/mol for All-Trans-Retinol. This activation energy is similar to ∼17 kcal/mol obtained experimentally for the isomerization reaction in RPE microsomes. Mass spectrome...
Gabriel H Travis - One of the best experts on this subject based on the ideXlab platform.
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non photopic and photopic visual cycles differentially regulate immediate early and late phases of cone photoreceptor mediated vision
Journal of Biological Chemistry, 2020Co-Authors: Rebecca Ward, Diego Cobice, Dionissia A Pepe, Eoghan M Mcgarrigle, Susan E Brockerhoff, Gabriel H Travis, Joanna J Kaylor, James B Hurley, Breandan N KennedyAbstract:Cone photoreceptors in the retina enable vision over a wide range of light intensities. However, the processes enabling cone vision in bright light (i.e. photopic vision) are not adequately understood. Chromophore regeneration of cone photopigments may require the retinal pigment epithelium (RPE) and/or retinal Muller glia. In the RPE, isomerization of all-trans-retinyl esters (atRE) to 11-cis-retinol (11cROL) is mediated by the retinoid isomerohydrolase Rpe65. A putative alternative retinoid isomerase, dihydroceramide desaturase-1 (DES1), is expressed in RPE and Muller cells. The retinol-isomerase activities of Rpe65 and Des1 are inhibited by emixustat and fenretinide, respectively. Here, we tested the effects of these visual cycle inhibitors on immediate, early and late phases of cone photopic vision. In zebrafish larvae raised under cyclic light conditions, fenretinide impaired late cone photopic vision, whereas emixustat-treated zebrafish unexpectedly had normal vision. In contrast, emixustat-treated larvae raised under extensive dark-adaption displayed significantly attenuated immediate photopic vision concomitant with significantly reduced 11-cis-retinaldehyde (11cRAL). Following 30 minutes of light, early photopic vision recovered, despite 11cRAL levels remaining significantly reduced. Defects in immediate cone photopic vision were rescued in emixustat- or fenretinide-treated larvae following exogenous 9-cis-retinaldehyde (9cRAL) supplementation. Genetic knockout of Des1 (degs1) or retinaldehyde-binding protein 1b (rlbp1b) did not eliminate photopic vision in zebrafish. Our findings define molecular and temporal requirements of the non-photopic or photopic visual cycles for mediating vision in bright light.
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non photopic and photopic visual cycles differentially regulate immediate early and late phases of cone photoreceptor mediated vision
bioRxiv, 2020Co-Authors: Rebecca Ward, Diego Cobice, Dionissia A Pepe, Eoghan M Mcgarrigle, Susan E Brockerhoff, Gabriel H Travis, Joanna J Kaylor, James B Hurley, Breandan N KennedyAbstract:Cone photoreceptors in the retina enable vision over a wide range of light intensities. However, the processes enabling cone vision in bright light (i.e. photopic vision) are not adequately understood. Chromophore regeneration of cone photopigments may require the retinal pigment epithelium (RPE) and/or retinal Muller glia. In the RPE, isomerization of all-trans-retinyl esters (atRE) to 11-cis-retinol (11cROL) is mediated by the retinoid isomerohydrolase Rpe65. An alternative retinoid isomerase, dihydroceramide desaturase-1 (DES1), is expressed in RPE and Muller cells. The retinol-isomerase activities of Rpe65 and Des1 are inhibited by emixustat and fenretinide, respectively. Here, we tested the effects of these visual cycle inhibitors on immediate, early and late phases of cone photopic vision. In zebrafish larvae raised under cyclic light conditions, fenretinide impaired late cone photopic vision, whereas emixustat-treated zebrafish unexpectedly had normal vision. In contrast, emixustat-treated larvae raised under extensive dark-adaption displayed significantly attenuated immediate photopic vision concomitantly with significantly reduced 11-cis-retinaldehyde (11cRAL). Following 30 minutes of light, early photopic vision recovered, despite 11cRAL levels remaining significantly reduced. Defects in immediate cone photopic vision were rescued in emixustat- or fenretinide-treated larvae following exogenous 9-cis-retinaldehyde (9cRAL) supplementation. Genetic knockout of degs1 or retinaldehyde-binding protein 1b (rlbp1b) revealed that neither are required for photopic vision in zebrafish. Our findings define the molecular and temporal requirements of the non-photopic and photopic visual cycles for mediating vision in bright light.
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diacylglycerol o acyltransferase type 1 synthesizes retinyl esters in the retina and retinal pigment epithelium
PLOS ONE, 2015Co-Authors: Joanna J Kaylor, Roxana A. Radu, Nicholas Bischoff, Jacob Makshanoff, Jane Hu, Marcia Lloyd, Shannan Eddington, Tran Bianconi, Gabriel H TravisAbstract:Retinyl esters represent an insoluble storage form of vitamin A and are substrates for the retinoid isomerase (Rpe65) in cells of the retinal pigment epithelium (RPE). The major retinyl-ester synthase in RPE cells is lecithin:retinol acyl-transferase (LRAT). A second palmitoyl coenzyme A-dependent retinyl-ester synthase activity has been observed in RPE homogenates but the protein responsible has not been identified. Here we show that diacylglycerol O-acyltransferase-1 (DGAT1) is expressed in multiple cells of the retina including RPE and Muller glial cells. DGAT1 catalyzes the synthesis of retinyl esters from multiple retinol isomers with similar catalytic efficiencies. Loss of DGAT1 in dgat1 -/- mice has no effect on retinal anatomy or the ultrastructure of photoreceptor outer-segments (OS) and RPE cells. Levels of visual chromophore in dgat1 -/- mice were also normal. However, the normal build-up of all-trans-retinyl esters (all-trans-RE’s) in the RPE during the first hour after a deep photobleach of visual pigments in the retina was not seen in dgat1 -/- mice. Further, total retinyl-ester synthase activity was reduced in both dgat1 -/- retina and RPE.
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Chicken Retinas Contain a Retinoid Isomerase Activity that Catalyzes the Direct Conversion of All-Trans-Retinol to 11-cis-Retinol
Biochemistry, 2005Co-Authors: Nathan L. Mata, Alberto Ruiz, Roxana A. Radu, Gabriel H TravisAbstract:Vertebrate retinas contain two types of light-detecting cells. Rods subserve vision in dim light, while cones provide color vision in bright light. Both contain light-sensitive proteins called opsins. The light-absorbing chromophore in most opsins is 11-cis-retinaldehyde, which is isomerized to all-trans-retinaldehyde by absorption of a photon. Restoration of light sensitivity requires chemical re-isomerization of retinaldehyde by an enzymatic pathway called the visual cycle in the retinal pigment epithelium. The isomerase in this pathway uses all-trans-retinyl esters synthesized by lecithin retinol acyl transferase (LRAT) as the substrate. Several lines of evidence suggest that cone opsins regenerate by a different mechanism. Here we demonstrate the existence of two catalytic activities in chicken retinas. The first is an isomerase activity that effects interconversion of All-Trans-Retinol and 11-cis-retinol. The second is an ester synthase that effects palmitoyl coenzyme A-dependent synthesis of all-tra...
Joanna J Kaylor - One of the best experts on this subject based on the ideXlab platform.
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non photopic and photopic visual cycles differentially regulate immediate early and late phases of cone photoreceptor mediated vision
Journal of Biological Chemistry, 2020Co-Authors: Rebecca Ward, Diego Cobice, Dionissia A Pepe, Eoghan M Mcgarrigle, Susan E Brockerhoff, Gabriel H Travis, Joanna J Kaylor, James B Hurley, Breandan N KennedyAbstract:Cone photoreceptors in the retina enable vision over a wide range of light intensities. However, the processes enabling cone vision in bright light (i.e. photopic vision) are not adequately understood. Chromophore regeneration of cone photopigments may require the retinal pigment epithelium (RPE) and/or retinal Muller glia. In the RPE, isomerization of all-trans-retinyl esters (atRE) to 11-cis-retinol (11cROL) is mediated by the retinoid isomerohydrolase Rpe65. A putative alternative retinoid isomerase, dihydroceramide desaturase-1 (DES1), is expressed in RPE and Muller cells. The retinol-isomerase activities of Rpe65 and Des1 are inhibited by emixustat and fenretinide, respectively. Here, we tested the effects of these visual cycle inhibitors on immediate, early and late phases of cone photopic vision. In zebrafish larvae raised under cyclic light conditions, fenretinide impaired late cone photopic vision, whereas emixustat-treated zebrafish unexpectedly had normal vision. In contrast, emixustat-treated larvae raised under extensive dark-adaption displayed significantly attenuated immediate photopic vision concomitant with significantly reduced 11-cis-retinaldehyde (11cRAL). Following 30 minutes of light, early photopic vision recovered, despite 11cRAL levels remaining significantly reduced. Defects in immediate cone photopic vision were rescued in emixustat- or fenretinide-treated larvae following exogenous 9-cis-retinaldehyde (9cRAL) supplementation. Genetic knockout of Des1 (degs1) or retinaldehyde-binding protein 1b (rlbp1b) did not eliminate photopic vision in zebrafish. Our findings define molecular and temporal requirements of the non-photopic or photopic visual cycles for mediating vision in bright light.
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non photopic and photopic visual cycles differentially regulate immediate early and late phases of cone photoreceptor mediated vision
bioRxiv, 2020Co-Authors: Rebecca Ward, Diego Cobice, Dionissia A Pepe, Eoghan M Mcgarrigle, Susan E Brockerhoff, Gabriel H Travis, Joanna J Kaylor, James B Hurley, Breandan N KennedyAbstract:Cone photoreceptors in the retina enable vision over a wide range of light intensities. However, the processes enabling cone vision in bright light (i.e. photopic vision) are not adequately understood. Chromophore regeneration of cone photopigments may require the retinal pigment epithelium (RPE) and/or retinal Muller glia. In the RPE, isomerization of all-trans-retinyl esters (atRE) to 11-cis-retinol (11cROL) is mediated by the retinoid isomerohydrolase Rpe65. An alternative retinoid isomerase, dihydroceramide desaturase-1 (DES1), is expressed in RPE and Muller cells. The retinol-isomerase activities of Rpe65 and Des1 are inhibited by emixustat and fenretinide, respectively. Here, we tested the effects of these visual cycle inhibitors on immediate, early and late phases of cone photopic vision. In zebrafish larvae raised under cyclic light conditions, fenretinide impaired late cone photopic vision, whereas emixustat-treated zebrafish unexpectedly had normal vision. In contrast, emixustat-treated larvae raised under extensive dark-adaption displayed significantly attenuated immediate photopic vision concomitantly with significantly reduced 11-cis-retinaldehyde (11cRAL). Following 30 minutes of light, early photopic vision recovered, despite 11cRAL levels remaining significantly reduced. Defects in immediate cone photopic vision were rescued in emixustat- or fenretinide-treated larvae following exogenous 9-cis-retinaldehyde (9cRAL) supplementation. Genetic knockout of degs1 or retinaldehyde-binding protein 1b (rlbp1b) revealed that neither are required for photopic vision in zebrafish. Our findings define the molecular and temporal requirements of the non-photopic and photopic visual cycles for mediating vision in bright light.
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diacylglycerol o acyltransferase type 1 synthesizes retinyl esters in the retina and retinal pigment epithelium
PLOS ONE, 2015Co-Authors: Joanna J Kaylor, Roxana A. Radu, Nicholas Bischoff, Jacob Makshanoff, Jane Hu, Marcia Lloyd, Shannan Eddington, Tran Bianconi, Gabriel H TravisAbstract:Retinyl esters represent an insoluble storage form of vitamin A and are substrates for the retinoid isomerase (Rpe65) in cells of the retinal pigment epithelium (RPE). The major retinyl-ester synthase in RPE cells is lecithin:retinol acyl-transferase (LRAT). A second palmitoyl coenzyme A-dependent retinyl-ester synthase activity has been observed in RPE homogenates but the protein responsible has not been identified. Here we show that diacylglycerol O-acyltransferase-1 (DGAT1) is expressed in multiple cells of the retina including RPE and Muller glial cells. DGAT1 catalyzes the synthesis of retinyl esters from multiple retinol isomers with similar catalytic efficiencies. Loss of DGAT1 in dgat1 -/- mice has no effect on retinal anatomy or the ultrastructure of photoreceptor outer-segments (OS) and RPE cells. Levels of visual chromophore in dgat1 -/- mice were also normal. However, the normal build-up of all-trans-retinyl esters (all-trans-RE’s) in the RPE during the first hour after a deep photobleach of visual pigments in the retina was not seen in dgat1 -/- mice. Further, total retinyl-ester synthase activity was reduced in both dgat1 -/- retina and RPE.
Breandan N Kennedy - One of the best experts on this subject based on the ideXlab platform.
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non photopic and photopic visual cycles differentially regulate immediate early and late phases of cone photoreceptor mediated vision
Journal of Biological Chemistry, 2020Co-Authors: Rebecca Ward, Diego Cobice, Dionissia A Pepe, Eoghan M Mcgarrigle, Susan E Brockerhoff, Gabriel H Travis, Joanna J Kaylor, James B Hurley, Breandan N KennedyAbstract:Cone photoreceptors in the retina enable vision over a wide range of light intensities. However, the processes enabling cone vision in bright light (i.e. photopic vision) are not adequately understood. Chromophore regeneration of cone photopigments may require the retinal pigment epithelium (RPE) and/or retinal Muller glia. In the RPE, isomerization of all-trans-retinyl esters (atRE) to 11-cis-retinol (11cROL) is mediated by the retinoid isomerohydrolase Rpe65. A putative alternative retinoid isomerase, dihydroceramide desaturase-1 (DES1), is expressed in RPE and Muller cells. The retinol-isomerase activities of Rpe65 and Des1 are inhibited by emixustat and fenretinide, respectively. Here, we tested the effects of these visual cycle inhibitors on immediate, early and late phases of cone photopic vision. In zebrafish larvae raised under cyclic light conditions, fenretinide impaired late cone photopic vision, whereas emixustat-treated zebrafish unexpectedly had normal vision. In contrast, emixustat-treated larvae raised under extensive dark-adaption displayed significantly attenuated immediate photopic vision concomitant with significantly reduced 11-cis-retinaldehyde (11cRAL). Following 30 minutes of light, early photopic vision recovered, despite 11cRAL levels remaining significantly reduced. Defects in immediate cone photopic vision were rescued in emixustat- or fenretinide-treated larvae following exogenous 9-cis-retinaldehyde (9cRAL) supplementation. Genetic knockout of Des1 (degs1) or retinaldehyde-binding protein 1b (rlbp1b) did not eliminate photopic vision in zebrafish. Our findings define molecular and temporal requirements of the non-photopic or photopic visual cycles for mediating vision in bright light.
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non photopic and photopic visual cycles differentially regulate immediate early and late phases of cone photoreceptor mediated vision
bioRxiv, 2020Co-Authors: Rebecca Ward, Diego Cobice, Dionissia A Pepe, Eoghan M Mcgarrigle, Susan E Brockerhoff, Gabriel H Travis, Joanna J Kaylor, James B Hurley, Breandan N KennedyAbstract:Cone photoreceptors in the retina enable vision over a wide range of light intensities. However, the processes enabling cone vision in bright light (i.e. photopic vision) are not adequately understood. Chromophore regeneration of cone photopigments may require the retinal pigment epithelium (RPE) and/or retinal Muller glia. In the RPE, isomerization of all-trans-retinyl esters (atRE) to 11-cis-retinol (11cROL) is mediated by the retinoid isomerohydrolase Rpe65. An alternative retinoid isomerase, dihydroceramide desaturase-1 (DES1), is expressed in RPE and Muller cells. The retinol-isomerase activities of Rpe65 and Des1 are inhibited by emixustat and fenretinide, respectively. Here, we tested the effects of these visual cycle inhibitors on immediate, early and late phases of cone photopic vision. In zebrafish larvae raised under cyclic light conditions, fenretinide impaired late cone photopic vision, whereas emixustat-treated zebrafish unexpectedly had normal vision. In contrast, emixustat-treated larvae raised under extensive dark-adaption displayed significantly attenuated immediate photopic vision concomitantly with significantly reduced 11-cis-retinaldehyde (11cRAL). Following 30 minutes of light, early photopic vision recovered, despite 11cRAL levels remaining significantly reduced. Defects in immediate cone photopic vision were rescued in emixustat- or fenretinide-treated larvae following exogenous 9-cis-retinaldehyde (9cRAL) supplementation. Genetic knockout of degs1 or retinaldehyde-binding protein 1b (rlbp1b) revealed that neither are required for photopic vision in zebrafish. Our findings define the molecular and temporal requirements of the non-photopic and photopic visual cycles for mediating vision in bright light.
