scholarly journals Vitamin A aldehyde-taurine adduct and the visual cycle

2020 ◽  
Vol 117 (40) ◽  
pp. 24867-24875
Author(s):  
Hye Jin Kim ◽  
Jin Zhao ◽  
Janet R. Sparrow
Keyword(s):  
Schiff Base ◽  
Vitamin A ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Photoreceptor Cells ◽  
Light Sensitivity ◽  
Retinal Pigment Epithelial Cells ◽  
Photon Absorption ◽  
Visual Cycle ◽  
Covalently Linked

Visual pigment consists of opsin covalently linked to the vitamin A-derived chromophore, 11-cis-retinaldehyde. Photon absorption causes the chromophore to isomerize from the 11-cis- to all-trans-retinal configuration. Continued light sensitivity necessitates the regeneration of 11-cis-retinal via a series of enzyme-catalyzed steps within the visual cycle. During this process, vitamin A aldehyde is shepherded within photoreceptors and retinal pigment epithelial cells to facilitate retinoid trafficking, to prevent nonspecific reactivity, and to conserve the 11-cis configuration. Here we show that redundancy in this system is provided by a protonated Schiff base adduct of retinaldehyde and taurine (A1-taurine, A1T) that forms reversibly by nonenzymatic reaction. A1T was present as 9-cis, 11-cis, 13-cis, and all-trans isomers, and the total levels were higher in neural retina than in retinal pigment epithelium (RPE). A1T was also more abundant under conditions in which 11-cis-retinaldehyde was higher; this included black versus albino mice, dark-adapted versus light-adapted mice, and mice carrying the Rpe65-Leu450 versus Rpe65-450Met variant. Taurine levels paralleled these differences in A1T. Moreover, A1T was substantially reduced in mice deficient in the Rpe65 isomerase and in mice deficient in cellular retinaldehyde-binding protein; in these models the production of 11-cis-retinal is compromised. A1T is an amphiphilic small molecule that may represent a mechanism for escorting retinaldehyde. The transient Schiff base conjugate that the primary amine of taurine forms with retinaldehyde would readily hydrolyze to release the retinoid and thus may embody a pool of 11-cis-retinal that can be marshalled in photoreceptor cells.

scholarly journals Retinoids in the visual cycle: Role of the retinal G protein-coupled receptor

2020 ◽  
pp. jlr.TR120000850 ◽  
Author(s):  
Elliot H Choi ◽  
Anahita Daruwalla ◽  
Susie Suh ◽  
Henri Leinonen ◽  
Krzysztof Palczewski
Keyword(s):  
G Protein ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Light Sensitivity ◽  
Visual Signal ◽  
Enzymatic Reactions ◽  
Visual Cycle ◽  
Retinal Regeneration ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

Driven by the energy of a photon, the visual pigments in rod and cone photoreceptor cells isomerize 11-cis-retinal to the all-trans configuration. This photochemical reaction initiates the signal transduction pathway that eventually leads to the transmission of a visual signal to the brain and leaves the opsins insensitive to further light stimulation. For the eye to restore light sensitivity, opsins require recharging with 11-cis-retinal. This trans–cis back conversion is achieved through a series of enzymatic reactions composing the retinoid (visual) cycle. Although it is evident that the classical retinoid cycle is critical for vision, the existence of an adjunct pathway for 11-cis-retinal regeneration has been debated for many years. Retinal pigment epithelium (RPE)–retinal G protein-coupled receptor (RGR) has been identified previously as a mammalian retinaldehyde photoisomerase homologous to retinochrome found in invertebrates. Using pharmacological, genetic, and biochemical approaches, researchers have now established the physiological relevance of the RGR in 11-cis-retinal regeneration. The photoisomerase activity of RGR in the RPE and Müller glia explains how the eye can remain responsive in daylight. In this review, we will focus on retinoid metabolism in the eye and visual chromophore regeneration mediated by RGR.  

scholarly journals Bisretinoids of the Retina: Photo-Oxidation, Iron-Catalyzed Oxidation, and Disease Consequences

Antioxidants ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1382
Author(s):  
Hye Jin Kim ◽  
Diego Montenegro ◽  
Jin Zhao ◽  
Janet R. Sparrow
Keyword(s):  
Vitamin A ◽  
Retinal Pigment Epithelial ◽  
Retinal Pigment ◽  
Retinal Disease ◽  
Photoreceptor Cells ◽  
Retinal Pigment Epithelial Cells ◽  
Rpe Cells ◽  
Pigment Epithelial ◽  
Energy And Electron Transfer ◽  
Fluorescent Molecules

The retina and, in particular, retinal pigment epithelial cells are unusual for being encumbered by exposure to visible light, while being oxygen-rich, and also amassing photoreactive molecules. These fluorophores (bisretinoids) are generated as a byproduct of the activity of vitamin A aldehyde—the chromophore necessary for vision. Bisretinoids form in photoreceptor cells due to random reactions of two molecules of vitamin A aldehyde with phosphatidylethanolamine; bisretinoids are subsequently transferred to retinal pigment epithelial (RPE) cells, where they accumulate in the lysosomal compartment with age. Bisretinoids can generate reactive oxygen species by both energy and electron transfer, and they become photo-oxidized and photolyzed in the process. While these fluorescent molecules are accrued by RPE cells of all healthy eyes, they are also implicated in retinal disease.

scholarly journals The Impact of the Timing of Dosing on the Severity of UNC569-Induced Ultrastructural Changes in the Mouse Retina

2020 ◽  
Vol 48 (5) ◽  
pp. 669-676
Author(s):  
Ayako Sayama ◽  
Keiko Okado ◽  
Mayu Yamaguchi ◽  
Naozumi Samata ◽  
Masako Imaoka ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Electron Microscopic Examination ◽  
Photoreceptor Cells ◽  
Ultrastructural Changes ◽  
Mouse Retina ◽  
Visual Cycle ◽  
Electron Microscopic ◽  
The Impact

Mer proto-oncogene tyrosine kinase (MerTK), expressed in the retinal pigment epithelium (RPE), regulates the phagocytosis of shed photoreceptor outer segments. To investigate the influence of dosing time on MerTK inhibitor UNC569-induced retinal toxicity, UNC569 at 100 mg/kg was orally administered to male mice at 2 different Zeitgeber times (ZT5.5 or ZT22) for 28 days. Electron microscopy was conducted at ZT2 after the final dosing. Additionally, the visual cycle components (11-cis-retinal, all-trans-retinal, all-trans-retinol, and 11-cis-retinol), which play an important role in maintaining retinal homeostasis, were quantified by liquid chromatography/mass spectrometry/mass spectrometry. Under electron microscopic examination, the number of phagosomes and phagolysosomes in the RPE increased in both the ZT5.5 and ZT22 administered groups, while endoplasmic reticulum dilatation in the RPE and chromatin aggregation of photoreceptor nuclei were observed only in the ZT22 administered group. No change was observed in any of the visual cycle components. These results suggest that the timing of the dosing in relation to the physiological MerTK phosphorylation affected the severity of changes in the RPE, leading to the apoptosis of the photoreceptor cells.

scholarly journals Bisretinoid phospholipid and vitamin A aldehyde: Shining a light

2020 ◽  
pp. jlr.TR120000742 ◽  
Author(s):  
Hye Jin Kim ◽  
Janet R Sparrow
Keyword(s):  
Vitamin A ◽  
Retinal Pigment ◽  
Photoreceptor Cells ◽  
Photon Absorption ◽  
Lipid Phase ◽  
New Findings ◽  
Acyl Chains ◽  
Retinal Chromophore ◽  
Reversible Formation ◽  
Multiple Species

Vitamin A aldehyde covalently bound to opsin protein is embedded in a phospholipid-rich membrane that supports photon absorption and phototransduction in photoreceptor cell outer segments. Following absorption of a photon, the 11-cis-retinal chromophore of visual pigment in photoreceptor cells isomerizes to all-trans-retinal. To maintain photosensitivity 11-cis-retinal must be replaced. At the same time, however, all-trans-retinal has to be handled so as to prevent nonspecific aldehyde activity. Some molecules of retinaldehyde upon release from opsin are efficiently reduced to retinol. Other molecules are released into the lipid phase of the disc membrane where they form a conjugate (N-retinylidene-PE, NRPE) through a Schiff base linkage with phosphatidylethanolamine (PE). The reversible formation of NRPE serves as a transient sink for retinaldehyde that is intended to return retinaldehyde to the visual cycle. However, if instead of hydrolyzing to PE and retinaldehyde, NRPE reacts with a second molecule of retinaldehyde a synthetic pathway is initiated that leads to the formation of multiple species of unwanted bisretinoid fluorophores. We report on recently identified members of the bisretinoid family some of which differ with respect to the acyl chains associated with the glycerol backbone. We discuss processing of the lipid moieties of these fluorophores in lysosomes of retinal pigment epithelial (RPE) cells, their fluorescence characters and new findings related to light and iron-associated oxidation of bisretinoids.

Pigment Epithelium-Derived Factor: A Novel Therapeutic Target for Cardiometabolic Diseases and Related Complications

2018 ◽  
Vol 25 (13) ◽  
pp. 1480-1500 ◽  
Author(s):  
Sho-ichi Yamagishi ◽  
Takanori Matsui
Keyword(s):  
Cardiovascular Disease ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Visceral Obesity ◽  
Retinal Pigment Epithelial Cells ◽  
Atherosclerotic Cardiovascular Disease ◽  
Cardiometabolic Diseases ◽  
The Metabolic Syndrome ◽  
Pigment Epithelium Derived Factor ◽  
Cardiometabolic Disorders

Pigment epithelium-derived factor (PEDF) is a glycoprotein that belongs to the superfamily of serine protease inhibitors, serpins. It was first identified as a neuronal differentiating factor secreted by human retinal pigment epithelial cells, and then found to be the most potent inhibitor of pathological angiogenesis in mammalian eyes. Recently, PEDF has been shown not only to suppress oxidative stress and inflammatory reactions in vascular wall cells, T cells and macrophages, and adipocytes, but also to exert antithrombotic and anti-fibrotic properties, thereby protecting against the development and progression of various cardiometabolic diseases and related complications. Furthermore, accumulating evidence has suggested that circulating PEDF levels may be a biomarker of severity and prognosis of these devastating disorders. Number of subjects with visceral obesity and insulin resistance is increasing, and the metabolic syndrome and its related complications, such as diabetes, nonalcoholic fatty liver disease/non-alcoholic steatohepatits, and atherosclerotic cardiovascular disease are a growing health challenge. Therefore, in this study, we review the pathophysiological role of PEDF in obesity and metabolic disorders, cardiovascular disease, diabetic eye and kidney complications, liver diseases, and reproductive system disorders, and discuss the potential clinical utility of modulating the expression and actions of PEDF for preventing these cardiometabolic disorders. We also refer to the clinical value of PEDF as a biomarker in cardiometabolic complications.

scholarly journals A Splice Variant in SLC16A8 Gene Leads to Lactate Transport Deficit in Human iPS Cell-Derived Retinal Pigment Epithelial Cells

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 179
Author(s):  
Laurence Klipfel ◽  
Marie Cordonnier ◽  
Léa Thiébault ◽  
Emmanuelle Clérin ◽  
Frédéric Blond ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Pigment Epithelial Cells ◽  
Age Related Macular Degeneration ◽  
Lactate Transport ◽  
Ips Cell ◽  
Risk Alleles ◽  
Age Related ◽  
A Genome

Age-related macular degeneration (AMD) is a blinding disease for which most of the patients remain untreatable. Since the disease affects the macula at the center of the retina, a structure specific to the primate lineage, rodent models to study the pathophysiology of AMD and to develop therapies are very limited. Consequently, our understanding relies mostly on genetic studies highlighting risk alleles at many loci. We are studying the possible implication of a metabolic imbalance associated with risk alleles within the SLC16A8 gene that encodes for a retinal pigment epithelium (RPE)-specific lactate transporter MCT3 and its consequences for vision. As a first approach, we report here the deficit in transepithelial lactate transport of a rare SLC16A8 allele identified during a genome-wide association study. We produced induced pluripotent stem cells (iPSCs) from the unique patient in our cohort that carries two copies of this allele. After in vitro differentiation of the iPSCs into RPE cells and their characterization, we demonstrate that the rare allele results in the retention of intron 2 of the SLC16A8 gene leading to the absence of MCT3 protein. We show using a biochemical assay that these cells have a deficit in transepithelial lactate transport.

Retinol dehydrogenases: Membrane-bound enzymes for the visual function

2014 ◽  
Vol 92 (6) ◽  
pp. 510-523 ◽  
Author(s):  
Mustapha Lhor ◽  
Christian Salesse
Keyword(s):  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Membrane Binding ◽  
Large Family ◽  
Structural Features ◽  
Visual Cycle ◽  
Retinoid Metabolism ◽  
Current State ◽  
Membrane Bound ◽  
Membrane Bound Enzymes

Retinoid metabolism is important for many physiological functions, such as differenciation, growth, and vision. In the visual context, after the absorption of light in rod photoreceptors by the visual pigment rhodopsin, 11-cis retinal is isomerized to all-trans retinal. This retinoid subsequently undergoes a series of modifications during the visual cycle through a cascade of reactions occurring in photoreceptors and in the retinal pigment epithelium. Retinol dehydrogenases (RDHs) are enzymes responsible for crucial steps of this visual cycle. They belong to a large family of proteins designated as short-chain dehydrogenases/reductases. The structure of these RDHs has been predicted using modern bioinformatics tools, which allowed to propose models with similar structures including a common Rossman fold. These enzymes undergo oxidoreduction reactions, whose direction is dictated by the preference and concentration of their individual cofactor (NAD(H)/NADP(H)). This review presents the current state of knowledge on functional and structural features of RDHs involved in the visual cycle as well as knockout models. RDHs are described as integral or peripheral enzymes. A topology model of the membrane binding of these RDHs via their N- and (or) C-terminal domain has been proposed on the basis of their individual properties. Membrane binding is a crucial issue for these enzymes because of the high hydrophobicity of their retinoid substrates.

scholarly journals Pathophysiological features of the visual cycle, cascade and metabolic pathways in retinitis pigmentosa

2021 ◽  
Vol 14 (1) ◽  
pp. 80-88
Author(s):  
M. E. Weener ◽  
D. S. Atarshchikov ◽  
V. V. Kadyshev ◽  
I. V. Zolnikova ◽  
A. M. Demchinsky ◽  
...  
Keyword(s):  
Retinal Pigment Epithelium ◽  
Literature Review ◽  
Retinitis Pigmentosa ◽  
Metabolic Pathways ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Visual Signal ◽  
Visual Cycle ◽  
Target Treatment ◽  
Interphotoreceptor Matrix

This literature review offers a detailed description of the genes and proteins involved in pathophysiological processes in isolated retinitis pigmentosa (RP). To date, 84 genes and 7 candidate genes have been described for non-syndromic RP. Each of these genes encodes a protein that plays a role in vital processes in the retina and / or retinal pigment epithelium, including the cascade of phototransduction (transmission of the visual signal), the visual cycle, ciliary transport, the environment of photoreceptor cilia and the interphotoreceptor matrix. The identification and study of pathophysiological pathways affected in non-syndromic RP is important for understanding the main pathogenic ways and developing approaches to target treatment.

JAM-C maintains VEGR2 expression to promote retinal pigment epithelium cell survival under oxidative stress

2017 ◽  
Vol 117 (04) ◽  
pp. 750-757
Author(s):  
Xin Jia ◽  
Chen Zhao ◽  
Qishan Chen ◽  
Yuxiang Du ◽  
Lijuan Huang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Retinal Pigment Epithelium ◽  
Cell Survival ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Retinal Pigment Epithelium Cell ◽  
Photoreceptor Cells ◽  
Rpe Cells

SummaryJunctional adhesion molecule-C (JAM-C) has been shown to play critical roles during development and in immune responses. However, its role in adult eyes under oxidative stress remains poorly understood. Here, we report that JAM-C is abundantly expressed in adult mouse retinae and choroids in vivo and in cultured retinal pigment epithelium (RPE) and photoreceptor cells in vitro. Importantly, both JAM-C expression and its membrane localisation are downregulated by H2O2-induced oxidative stress. Under H2O2-induced oxidative stress, JAM-C is critically required for the survival of human RPE cells. Indeed, loss of JAM-C by siRNA knockdown decreased RPE cell survival. Mechanistically, we show that JAM-C is required to maintain VEGFR2 expression in RPE cells, and VEGFR2 plays an important role in keeping the RPE cells viable since overexpression of VEGFR2 partially restored impaired RPE survival caused by JAM-C knockdown and increased RPE survival. We further show that JAM-C regulates VEGFR2 expression and, in turn, modulates p38 phosphorylation. Together, our data demonstrate that JAM-C plays an important role in maintaining VEGR2 expression to promote RPE cell survival under oxidative stress. Given the vital importance of RPE in the eye, approaches that can modulate JAM-C expression may have therapeutic values in treating diseases with impaired RPE survival.

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