Membrane receptors and transporters involved in the function and transport of vitamin A and its derivatives.

The eye is the human organ most sensitive to vitamin A deficiency because of vision's absolute and heavy dependence on vitamin A for light perception. Studies of the molecular basis of vision have provided important insights into the intricate mechanistic details of the function, transport and recycling of vitamin A and its derivatives (retinoid). This review focuses on retinoid-related membrane receptors and transporters. Three kinds of mammalian membrane receptors and transporters are discussed: opsins, best known as vitamin A-based light sensors in vision; ABCA4, an ATP-dependent transporter specializes in the transport of vitamin A derivative; and STRA6, a recently identified membrane receptor that mediates cellular uptake of vitamin A. The evolutionary driving forces for their existence and the wide spectrum of human diseases associated with these proteins are discussed. Lessons learned from the study of the visual system might be useful for understanding retinoid biology and retinoid-related diseases in other organ systems as well. This article is part of a Special Issue entitled Retinoid and Lipid Metabolism.

[1]  D. Goodman 8 – Plasma Retinol-Binding Protein , 1984 .

[2]  J. Findlay,et al.  The mechanism of uptake of retinol by plasma-membrane vesicles. , 1988, The Biochemical journal.

[3]  D. Oprian,et al.  Salamander UV cone pigment: Sequence, expression, and spectral properties , 2001, Visual Neuroscience.

[4]  D. Goodman PLASMA RETINOL‐BINDING PROTEIN * , 1980, Annals of the New York Academy of Sciences.

[5]  J. Horwitz,et al.  Interactions of all-trans, 9-, 11-, and 13-cis-retinal, all-trans-retinyl acetate, and retinoic acid with human retinol-binding protein and prealbumin. , 1973, The Journal of biological chemistry.

[6]  K. Palczewski,et al.  Limited roles of Rdh8, Rdh12, and Abca4 in all-trans-retinal clearance in mouse retina. , 2009, Investigative ophthalmology & visual science.

[7]  Gregor Eichele,et al.  9-cis retinoic acid is a high affinity ligand for the retinoid X receptor , 1992, Cell.

[8]  R. Regan,et al.  First implication of STRA6 mutations in isolated anophthalmia, microphthalmia, and coloboma: A new dimension to the STRA6 phenotype , 2011, Human mutation.

[9]  Y. Oda,et al.  Dependency on light and vitamin A derivatives of the biogenesis of 3- hydroxyretinal and visual pigment in the compound eyes of Drosophila melanogaster , 1988, The Journal of general physiology.

[10]  Sulin Jiang,et al.  Location and Functional Significance of Retinol-binding Sites on the Serine/Threonine Kinase, c-Raf* , 2005, Journal of Biological Chemistry.

[11]  K. Foster,et al.  Transducin Activation by the Bovine Opsin Apoprotein (*) , 1995, The Journal of Biological Chemistry.

[12]  D. Ong,et al.  Differential interaction of lecithin-retinol acyltransferase with cellular retinol binding proteins. , 1992, Biochemistry.

[13]  Lu Chen,et al.  Synaptic Signaling by All-Trans Retinoic Acid in Homeostatic Synaptic Plasticity , 2008, Neuron.

[14]  A. Slavotinek,et al.  Two novel STRA6 mutations in a patient with anophthalmia and diaphragmatic eventration , 2009, American journal of medical genetics. Part A.

[15]  H Gobind Khorana,et al.  Rhodopsin structure, dynamics, and activation: a perspective from crystallography, site-directed spin labeling, sulfhydryl reactivity, and disulfide cross-linking. , 2003, Advances in protein chemistry.

[16]  A. Munnich,et al.  Matthew-Wood syndrome is caused by truncating mutations in the retinol-binding protein receptor gene STRA6. , 2007, American journal of human genetics.

[17]  K. Nakanishi,et al.  Isolation and one-step preparation of A2E and iso-A2E, fluorophores from human retinal pigment epithelium. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[18]  R. Molday,et al.  The Effect of Lipid Environment and Retinoids on the ATPase Activity of ABCR, the Photoreceptor ABC Transporter Responsible for Stargardt Macular Dystrophy* , 2000, The Journal of Biological Chemistry.

[19]  J. Heller,et al.  Uptake of retinol and retinoic acid from serum retinol-binding protein by retinal pigment epithelial cells. , 1977, The Journal of biological chemistry.

[20]  Tao Wang,et al.  Requirement for an Enzymatic Visual Cycle in Drosophila , 2010, Current Biology.

[21]  J. Lupski,et al.  Null missense ABCR (ABCA4) mutations in a family with stargardt disease and retinitis pigmentosa. , 2001, Investigative ophthalmology & visual science.

[22]  L. Molday,et al.  The 220-kDa Rim Protein of Retinal Rod Outer Segments Is a Member of the ABC Transporter Superfamily* , 1997, The Journal of Biological Chemistry.

[23]  A. Sommer Vitamin A Status, Resistance to Infection, and Childhood Mortality a , 1990, Annals of the New York Academy of Sciences.

[24]  Xinran Liu,et al.  Isotretinoin treatment inhibits lipofuscin accumulation in a mouse model of recessive Stargardt's macular degeneration. , 2004, Novartis Foundation symposium.

[25]  M. Holick Vitamin D: evolutionary, physiological and health perspectives. , 2011, Current drug targets.

[26]  D. Bok,et al.  The renewal of diffusely distributed protein in the outer segments of rods and cones. , 1972, Vision research.

[27]  B. Rittmann,et al.  Enzymatic degradation of A2E, a retinal pigment epithelial lipofuscin bisretinoid. , 2011, Journal of the American Chemical Society.

[28]  G. Eldred,et al.  Retinal age pigments generated by self-assembling lysosomotropic detergents , 1993, Nature.

[29]  R. Blomhoff Vitamin A in Health and Disease , 1994 .

[30]  J. Sparrow,et al.  Interpretations of fundus autofluorescence from studies of the bisretinoids of the retina. , 2010, Investigative ophthalmology & visual science.

[31]  Jay Neitz,et al.  Gene therapy for red-green colour blindness in adult primates , 2009, Nature.

[32]  L. Molday,et al.  ABCR expression in foveal cone photoreceptors and its role in Stargardt macular dystrophy , 2000, Nature Genetics.

[33]  George Wald,et al.  CHAPTER 7 – The Distribution and Evolution of Visual Systems , 1960 .

[34]  J. Grippo,et al.  9-Cis retinoic acid stereoisomer binds and activates the nuclear receptor RXRα , 1992, Nature.

[35]  W. P. Hayes,et al.  Melanopsin: An opsin in melanophores, brain, and eye. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[36]  J. Nathans The Evolution and Physiology of Human Color Vision Insights from Molecular Genetic Studies of Visual Pigments , 1999, Neuron.

[37]  T. Terasaki,et al.  Retinal‐specific ATP‐binding cassette transporter (ABCR/ABCA4) is expressed at the choroid plexus in rat brain , 2005, Journal of neurochemistry.

[38]  J. Nathans,et al.  Retinal Stimulates ATP Hydrolysis by Purified and Reconstituted ABCR, the Photoreceptor-specific ATP-binding Cassette Transporter Responsible for Stargardt Disease* , 1999, The Journal of Biological Chemistry.

[39]  D. Bok,et al.  Promotion of the release of 11-cis-retinal from cultured retinal pigment epithelium by interphotoreceptor retinoid-binding protein. , 1992, Biochemistry.

[40]  G. Wald The Molecular Basis of Visual Excitation , 1968, Nature.

[41]  K. Palczewski,et al.  Metabolic Basis of Visual Cycle Inhibition by Retinoid and Nonretinoid Compounds in the Vertebrate Retina* , 2008, Journal of Biological Chemistry.

[42]  Krzysztof Palczewski,et al.  G protein-coupled receptor rhodopsin. , 2006, Annual review of biochemistry.

[43]  F. Formelli,et al.  Retinoids: in vitro interaction with retinol‐binding protein and influence on plasma retinol , 1993, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[44]  C. Bates Vitamin A , 1995, The Lancet.

[45]  C. Stephensen Vitamin A, infection, and immune function. , 2001, Annual review of nutrition.

[46]  Satchidananda Panda,et al.  Melanopsin Is Required for Non-Image-Forming Photic Responses in Blind Mice , 2003, Science.

[47]  D. Bok,et al.  Reductions in serum vitamin A arrest accumulation of toxic retinal fluorophores: a potential therapy for treatment of lipofuscin-based retinal diseases. , 2005, Investigative ophthalmology & visual science.

[48]  E. Harrison,et al.  Mechanisms of provitamin A (carotenoid) and vitamin A (retinol) transport into and out of intestinal Caco-2 cells Published, JLR Papers in Press, August 2, 2007. , 2007, Journal of Lipid Research.

[49]  K. Hiraki,et al.  4-Hydroxyretinal, a new visual pigment chromophore found in the bioluminescent squid, Watasenia scintillans. , 1988, Biochimica et biophysica acta.

[50]  R. Regan,et al.  First implication of STRA 6 mutations in isolated anophthalmia , microphthalmia and coloboma : a new dimension to the STRA 6 phenotype , 2014 .

[51]  J. Spudich,et al.  Retinylidene proteins: structures and functions from archaea to humans. , 2000, Annual review of cell and developmental biology.

[52]  A. Ross,et al.  Vitamin A Status: Relationship to Immunity and the Antibody Response , 1992, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[53]  B. J. Klevering,et al.  Autosomal-Recessive Retinitis Pigmentosa , 2010 .

[54]  T. Sano,et al.  A novel retinoic acid analogue, 7-hydroxy retinoic acid, isolated from cyanobacteria. , 2011, Biochimica et biophysica acta.

[55]  J. Nathans,et al.  Molecular genetics of human color vision: the genes encoding blue, green, and red pigments. , 1986, Science.

[56]  R. Molday,et al.  Binding of retinoids to ABCA4, the photoreceptor ABC transporter associated with Stargardt macular degeneration. , 2010, Methods in molecular biology.

[57]  A. Ross,et al.  Diet in vitamin A research. , 2010, Methods in molecular biology.

[58]  D. Bok,et al.  Complement System Dysregulation and Inflammation in the Retinal Pigment Epithelium of a Mouse Model for Stargardt Macular Degeneration* , 2011, The Journal of Biological Chemistry.

[59]  Jeannie Chen,et al.  A photic visual cycle of rhodopsin regeneration is dependent on Rgr , 2001, Nature Genetics.

[60]  L. Molday,et al.  Role of the C Terminus of the Photoreceptor ABCA4 Transporter in Protein Folding, Function, and Retinal Degenerative Diseases* , 2009, Journal of Biological Chemistry.

[61]  S. Ottonello,et al.  Vitamin A uptake from retinol-binding protein in a cell-free system from pigment epithelial cells of bovine retina. Retinol transfer from plasma retinol-binding protein to cytoplasmic retinol-binding protein with retinyl-ester formation as the intermediate step. , 1987, The Journal of biological chemistry.

[62]  J. von Lintig,et al.  A class B scavenger receptor mediates the cellular uptake of carotenoids in Drosophila , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[63]  G. Travis,et al.  Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[64]  Jianbing Yan,et al.  Natural Genetic Variation in Lycopene Epsilon Cyclase Tapped for Maize Biofortification , 2008, Science.

[65]  K. Yau,et al.  Breaking the Covalent Bond— A Pigment Property that Contributes to Desensitization in Cones , 2005, Neuron.

[66]  G. Fain,et al.  Adaptation in vertebrate photoreceptors. , 2001, Physiological reviews.

[67]  J. Taylor,et al.  A Fish Eye Out of Water: Ten Visual Opsins in the Four-Eyed Fish, Anableps anableps , 2009, PloS one.

[68]  P. A. Peterson,et al.  In vitro uptake of vitamin A from the retinol-binding plasma protein to mucosal epithelial cells from the monkey's small intestine. , 1976, The Journal of biological chemistry.

[69]  Helen H. Hobbs,et al.  Identification of Scavenger Receptor SR-BI as a High Density Lipoprotein Receptor , 1996, Science.

[70]  U. Dräger Retinoic Acid Signaling in the Functioning Brain , 2006, Science's STKE.

[71]  K. Palczewski,et al.  Evolutionary analysis of rhodopsin and cone pigments: connecting the three‐dimensional structure with spectral tuning and signal transfer , 2003, FEBS letters.

[72]  M. Maden Retinoic acid in the development, regeneration and maintenance of the nervous system , 2007, Nature Reviews Neuroscience.

[73]  R. Metlapally,et al.  Identification of STRA6 and SKI sequence variants in patients with anophthalmia/microphthalmia , 2008, Molecular vision.

[74]  Akihisa Terakita,et al.  Parietal-Eye Phototransduction Components and Their Potential Evolutionary Implications , 2006, Science.

[75]  D. Hicks,et al.  The retinal pigment epithelium in health and disease. , 2010, Current molecular medicine.

[76]  B. Thiers Retinaldehyde represses adipogenesis and diet-induced obesity , 2008 .

[77]  Seth M. Klein,et al.  Analysis of chimeric receptors shows that multiple distinct functional activities of scavenger receptor, class B, type I (SR-BI), are localized to the extracellular receptor domain. , 2001, Biochemistry.

[78]  Gerald H. Jacobs,et al.  The evolution of Primate color vision. , 2009 .

[79]  G. Cutting Modifier genes in Mendelian disorders: the example of cystic fibrosis , 2010, Annals of the New York Academy of Sciences.

[80]  T. Wensel,et al.  The nature of dominant mutations of rhodopsin and implications for gene therapy , 2003, Molecular Neurobiology.

[81]  Jeremy Nathans,et al.  Biochemical defects in ABCR protein variants associated with human retinopathies , 2000, Nature Genetics.

[82]  J. Buck,et al.  Anhydroretinol induces oxidative stress and cell death. , 1999, Cancer research.

[83]  K. Hellingwerf,et al.  Photobiology of microorganisms: how photosensors catch a photon to initialize signalling , 1996, Molecular microbiology.

[84]  K. Hofmann,et al.  Opsin/all-trans-retinal complex activates transducin by different mechanisms than photolyzed rhodopsin. , 1996, Biochemistry.

[85]  J. Adams,et al.  Structure-activity and dose-response relationships in the neural and behavioral teratogenesis of retinoids. , 1993, Neurotoxicology and teratology.

[86]  J. Mandl,et al.  Ascorbate metabolism and its regulation in animals. , 1997, Free radical biology & medicine.

[87]  W. P. Hayes,et al.  A Novel Human Opsin in the Inner Retina , 2000, The Journal of Neuroscience.

[88]  Sumana Sanyal,et al.  Opsin Is a Phospholipid Flippase , 2011, Current Biology.

[89]  N. Takahashi,et al.  Retinoylation of proteins in mammalian cells. , 1996, Biochemical Society transactions.

[90]  K. Palczewski,et al.  Evaluation of potential therapies for a mouse model of human age-related macular degeneration caused by delayed all-trans-retinal clearance. , 2009, Investigative ophthalmology & visual science.

[91]  J. L. Napoli,et al.  Biochemical pathways of retinoid transport, metabolism, and signal transduction. , 1996, Clinical immunology and immunopathology.

[92]  J Nathans,et al.  Molecular genetics of human visual pigments. , 1992, Annual review of genetics.

[93]  J. Nathans,et al.  Molecular genetics of inherited variation in human color vision. , 1986, Science.

[94]  J Nathans,et al.  ROLE OF HYDROXYL‐BEARING AMINO ACIDS IN DIFFERENTIALLY TUNING THE ABSORPTION SPECTRA OF THE HUMAN RED AND GREEN CONE PIGMENTS , 1993, Photochemistry and photobiology.

[95]  W. Blaner Retinol-binding protein: the serum transport protein for vitamin A. , 1989, Endocrine reviews.

[96]  S. Kim,et al.  Experimental approaches to the study of A2E, a bisretinoid lipofuscin chromophore of retinal pigment epithelium. , 2010, Methods in molecular biology.

[97]  J. Nathans,et al.  Peropsin, a novel visual pigment-like protein located in the apical microvilli of the retinal pigment epithelium. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[98]  A. J. Roman,et al.  ABCA4 disease progression and a proposed strategy for gene therapy. , 2009, Human molecular genetics.

[99]  M. Biel,et al.  Melanopsin and rod–cone photoreceptive systems account for all major accessory visual functions in mice , 2003, Nature.

[100]  J. Findlay,et al.  The Transfer of Retinol from Serum Retinol-binding Protein to Cellular Retinol-binding Protein Is Mediated by a Membrane Receptor* , 1998, The Journal of Biological Chemistry.

[101]  D. Birch,et al.  Insights into the Function of Rim Protein in Photoreceptors and Etiology of Stargardt's Disease from the Phenotype in abcr Knockout Mice , 1999, Cell.

[102]  C. M. Davenport,et al.  Rhodopsin mutations in autosomal dominant retinitis pigmentosa. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[103]  G. Duester Retinoic Acid Synthesis and Signaling during Early Organogenesis , 2008, Cell.

[104]  Y. Jang,et al.  Complement activation by photooxidation products of A2E, a lipofuscin constituent of the retinal pigment epithelium , 2006, Proceedings of the National Academy of Sciences.

[105]  G. Travis,et al.  The photoreceptor rim protein is an ABC transporter encoded by the gene for recessive Stargardt's disease (ABCR) , 1997, FEBS letters.

[106]  A. Terakita,et al.  Identification and characterization of a protostome homologue of peropsin from a jumping spider , 2009, Journal of Comparative Physiology A.

[107]  J. Dowling,et al.  VITAMIN A DEFICIENCY AND NIGHT BLINDNESS. , 1958, Proceedings of the National Academy of Sciences of the United States of America.

[108]  Raag D. Airan,et al.  Temporally precise in vivo control of intracellular signalling , 2009, Nature.

[109]  P. Gouras,et al.  Impaired retinal function and vitamin A availability in mice lacking retinol‐binding protein , 1999, The EMBO journal.

[110]  J. Dowling,et al.  Chemistry of Visual Adaptation in the Rat , 1960, Nature.

[111]  J. Nathans,et al.  Mechanistic Studies of ABCR, the ABC Transporter in Photoreceptor Outer Segments Responsible for Autosomal Recessive Stargardt Disease , 2001, Journal of bioenergetics and biomembranes.

[112]  P. Sieving,et al.  Night Blindness and the Mechanism of Constitutive Signaling of Mutant G90D Rhodopsin , 2008, The Journal of Neuroscience.

[113]  J. von Lintig,et al.  NinaB combines carotenoid oxygenase and retinoid isomerase activity in a single polypeptide , 2008, Proceedings of the National Academy of Sciences.

[114]  Margaret A. Pericak-Vance,et al.  Genetic variants near TIMP3 and high-density lipoprotein–associated loci influence susceptibility to age-related macular degeneration , 2010, Proceedings of the National Academy of Sciences.

[115]  K. Palczewski,et al.  Involvement of All-trans-retinal in Acute Light-induced Retinopathy of Mice* , 2009, Journal of Biological Chemistry.

[116]  M. Drumm,et al.  Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease , 2009, Nature.

[117]  G. G. Stokes "J." , 1890, The New Yale Book of Quotations.

[118]  T. Sakmar,et al.  Interaction of A2E with Model Membranes. Implications to the Pathogenesis of Age-related Macular Degeneration , 2002, The Journal of general physiology.

[119]  Edward N Pugh,et al.  The Retinal G Protein-coupled Receptor (RGR) Enhances Isomerohydrolase Activity Independent of Light*[boxs] , 2005, Journal of Biological Chemistry.

[120]  K. Yau,et al.  Photon capture and signalling by melanopsin retinal ganglion cells , 2008, Nature.

[121]  H. Fong,et al.  Blue and ultraviolet light-absorbing opsin from the retinal pigment epithelium. , 1996, Biochemistry.

[122]  S. Kim,et al.  Complement activation by bisretinoid constituents of RPE lipofuscin. , 2009, Investigative ophthalmology & visual science.

[123]  H. Nau,et al.  Teratogenicity of vitamin A and retinoids. , 1994 .

[124]  G. H. Jacobs,et al.  Response to Comment on "Emergence of Novel Color Vision in Mice Engineered to Express a Human Cone Photopigment" , 2007, Science.

[125]  Krzysztof Palczewski,et al.  Noninvasive two-photon imaging reveals retinyl ester storage structures in the eye , 2004, The Journal of cell biology.

[126]  Aaron Y. Lee,et al.  Genome-wide association study of advanced age-related macular degeneration identifies a role of the hepatic lipase gene (LIPC) , 2010, Proceedings of the National Academy of Sciences.

[127]  R. Spencer,et al.  Visual function in patients with cone-rod dystrophy (CRD) associated with mutations in the ABCA4(ABCR) gene. , 2001, Experimental eye research.

[128]  M. Skinner,et al.  Characteristics of retinol accumulation from serum retinol-binding protein by cultured Sertoli cells. , 1989, Biochemistry.

[129]  Nimesh Mody,et al.  Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes , 2005, Nature.

[130]  A. Terakita,et al.  Bistable UV pigment in the lamprey pineal. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[131]  D. Phillips,et al.  The three-dimensional structure of an enzyme molecule. , 1966, Scientific American.

[132]  P. Chambon A decade of molecular biology of retinoic acid receptors , 1996, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[133]  T. Dryja,et al.  Molecular genetics of retinitis pigmentosa. , 1995, Human molecular genetics.

[134]  R. Lotan,et al.  Molecular Cloning and Characterization of a Novel Retinoic Acid-inducible Gene That Encodes a Putative G Protein-coupled Receptor* , 1998, The Journal of Biological Chemistry.

[135]  K. Palczewski,et al.  ISX is a retinoic acid‐sensitive gatekeeper that controls intestinal β,β‐carotene absorption and vitamin A production , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[136]  J. Khillan,et al.  Promotion of Feeder‐Independent Self‐Renewal of Embryonic Stem Cells by Retinol (Vitamin A) , 2008, Stem cells.

[137]  K. Palczewski,et al.  The ATP-binding cassette transporter ABCA4: structural and functional properties and role in retinal disease. , 2010, Advances in experimental medicine and biology.

[138]  D. Bok,et al.  Transport of retinol from the blood to the retina: an autoradiographic study of the pigment epithelial cell surface receptor for plasma retinol-binding protein. , 1976, Experimental eye research.

[139]  B. J. Klevering,et al.  Phenotypic spectrum of autosomal recessive cone-rod dystrophies caused by mutations in the ABCA4 (ABCR) gene. , 2002, Investigative ophthalmology & visual science.

[140]  R. Radu,et al.  Isomerization and Oxidation of Vitamin A in Cone-Dominant Retinas A Novel Pathway for Visual-Pigment Regeneration in Daylight , 2002, Neuron.

[141]  B. Zemelman,et al.  Selective Photostimulation of Genetically ChARGed Neurons , 2002, Neuron.

[142]  Transport and storage of vitamin A , 1990, Science.

[143]  F. Gage,et al.  An Essential Role for Retinoid Receptors RARβ and RXRγ In Long-Term Potentiation and Depression , 1998, Neuron.

[144]  Junping Gao,et al.  The Age Lipid A2E and Mitochondrial Dysfunction Synergistically Impair Phagocytosis by Retinal Pigment Epithelial Cells* , 2008, Journal of Biological Chemistry.

[145]  Y. Koutalos,et al.  Rapid formation of all-trans retinol after bleaching in frog and mouse rod photoreceptor outer segments , 2010, Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology.

[146]  G. Fain Chapter 27 Dark adaptation , 2001 .

[147]  R. Kawaguchi,et al.  An Essential Ligand-binding Domain in the Membrane Receptor for Retinol-binding Protein Revealed by Large-scale Mutagenesis and a Human Polymorphism* , 2008, Journal of Biological Chemistry.

[148]  A. Terakita,et al.  Diversity and functional properties of bistable pigments , 2010, Photochemical & photobiological sciences : Official journal of the European Photochemistry Association and the European Society for Photobiology.

[149]  M. Hill Intestinal flora and endogenous vitamin synthesis , 1997, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

[150]  H Nau,et al.  Teratogenicity of isotretinoin revisited: species variation and the role of all-trans-retinoic acid. , 2001, Journal of the American Academy of Dermatology.

[151]  R. Foster,et al.  A novel and ancient vertebrate opsin , 1997, FEBS letters.

[152]  M. Kane,et al.  Quantification of endogenous retinoids. , 2010, Methods in molecular biology.

[153]  D. Bok,et al.  Practical Remarks on Gout, Rheumatic Fever, and Chonic Rheumatism of the Joints; Being the Substance of the Croonian Lectures for the Present Year, Delivered at the College of Physicians , 1844, Edinburgh Medical and Surgical Journal.

[154]  A. Peterson,et al.  Retinoic acid from the meninges regulates cortical neuron generation. , 2009, Cell.

[155]  M. Alpern,et al.  Dark-light: model for nightblindness from the human rhodopsin Gly-90-->Asp mutation. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[156]  Toshiyuki Okano,et al.  Pinopsin is a chicken pineal photoreceptive molecule , 1994, Nature.

[157]  C. Montell,et al.  Dissection of the pathway required for generation of vitamin A and for Drosophila phototransduction , 2007, The Journal of cell biology.

[158]  D. Bok,et al.  The retinal pigment epithelium: a versatile partner in vision , 1993, Journal of Cell Science.

[159]  J. Nathans,et al.  Rhodopsin: structure, function, and genetics. , 1992, Biochemistry.

[160]  R. Molday,et al.  N-Retinylidene-phosphatidylethanolamine Is the Preferred Retinoid Substrate for the Photoreceptor-specific ABC Transporter ABCA4 (ABCR)* , 2004, Journal of Biological Chemistry.

[161]  Olivier Pourquié,et al.  Retinoic acid , 2008, Current Biology.

[162]  Satchidananda Panda,et al.  Illumination of the Melanopsin Signaling Pathway , 2005, Science.

[163]  T. Dryja,et al.  Mutations in RGR, encoding a light-sensitive opsin homologue, in patients with retinitis pigmentosa , 1999, Nature Genetics.

[164]  R. Allikmets,et al.  Further evidence for an association of ABCR alleles with age-related macular degeneration. The International ABCR Screening Consortium. , 2000, American journal of human genetics.

[165]  D. Berson,et al.  Phototransduction by Retinal Ganglion Cells That Set the Circadian Clock , 2002, Science.

[166]  J. L. Napoli,et al.  The Nuclear Transcription Factor RARα Associates with Neuronal RNA Granules and Suppresses Translation* , 2008, Journal of Biological Chemistry.

[167]  G. Zanotti,et al.  Plasma retinol-binding protein: structure and interactions with retinol, retinoids, and transthyretin. , 2004, Vitamins and hormones.

[168]  J. Dowling,et al.  Retinoic acid. A key molecule for eye and photoreceptor development. , 1997, Investigative ophthalmology & visual science.

[169]  H. Varmus,et al.  Changes in gene expression during the development of mammary tumors in MMTV-Wnt-1 transgenic mice , 2005, Genome Biology.

[170]  A. Philp,et al.  Novel retinal photoreceptors , 1998, Nature.

[171]  S. Tanumihardjo,et al.  Retinol to Retinol-Binding Protein (RBP) Is Low in Obese Adults due to Elevated apo-RBP , 2008, Experimental biology and medicine.

[172]  M. Newcomer,et al.  Plasma retinol binding protein: structure and function of the prototypic lipocalin. , 2000, Biochimica et biophysica acta.

[173]  H. Fong,et al.  The Endogenous Chromophore of Retinal G Protein-coupled Receptor Opsin from the Pigment Epithelium* , 1999, The Journal of Biological Chemistry.

[174]  K. Yau,et al.  Melanopsin-Containing Retinal Ganglion Cells: Architecture, Projections, and Intrinsic Photosensitivity , 2002, Science.

[175]  K. Palczewski,et al.  Retinopathy in Mice Induced by Disrupted All-trans-retinal Clearance* , 2008, Journal of Biological Chemistry.

[176]  K. Kubokawa,et al.  Amphioxus homologs of Go‐coupled rhodopsin and peropsin having 11‐cis‐ and all‐trans‐retinals as their chromophores , 2002, FEBS letters.

[177]  M. Dean,et al.  Retinitis pigmentosa caused by a homozygous mutation in the Stargardt disease gene ABCR , 1998, Nature Genetics.

[178]  K. Nakanishi,et al.  Intracellular signaling by 14-hydroxy-4,14-retro-retinol. , 1991, Science.

[179]  Y. Koutalos,et al.  Rod outer segment retinol formation is independent of Abca4, arrestin, rhodopsin kinase, and rhodopsin palmitylation. , 2011, Investigative ophthalmology & visual science.

[180]  B. Dass Night Blindness , 1876, The Indian medical gazette.

[181]  A. Myc,et al.  Differences in the action and metabolism between retinol and retinoic acid in B lymphocytes , 1991, The Journal of cell biology.

[182]  Russell G Foster,et al.  Neuropsin (Opn5): a novel opsin identified in mammalian neural tissue 1 , 2003, FEBS letters.

[183]  David W. Yandell,et al.  A point mutation of the rhodopsin gene in one form of retinitis pigmentosa , 1990, Nature.

[184]  J. Oram,et al.  The cell cholesterol exporter ABCA1 as a protector from cardiovascular disease and diabetes. , 2009, Biochimica et biophysica acta.

[185]  P. Calvas,et al.  Phenotypic spectrum of STRA6 mutations: from Matthew‐Wood syndrome to non‐lethal anophthalmia , 2009, Human mutation.

[186]  K. Yau,et al.  Signaling Properties of a Short-Wave Cone Visual Pigment and Its Role in Phototransduction , 2007, The Journal of Neuroscience.

[187]  P. A. Peterson,et al.  The retinol-binding protein. , 1980, Scandinavian journal of clinical and laboratory investigation. Supplementum.

[188]  J. Buck,et al.  Vitamin A in serum is a survival factor for fibroblasts. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[189]  Yoshihiro Kubo,et al.  A mammalian neural tissue opsin (Opsin 5) is a deep brain photoreceptor in birds , 2010, Proceedings of the National Academy of Sciences.

[190]  D. Bok,et al.  Accelerated accumulation of lipofuscin pigments in the RPE of a mouse model for ABCA4-mediated retinal dystrophies following Vitamin A supplementation. , 2008, Investigative ophthalmology & visual science.

[191]  K. Yau,et al.  Intrinsic Light Response of Retinal Horizontal Cells of Teleosts , 2009, Nature.

[192]  Solomon H. Snyder,et al.  Encephalopsin: A Novel Mammalian Extraretinal Opsin Discretely Localized in the Brain , 1999, The Journal of Neuroscience.

[193]  A. Tall,et al.  Role of HDL, ABCA1, and ABCG1 transporters in cholesterol efflux and immune responses. , 2010, Arteriosclerosis, thrombosis, and vascular biology.

[194]  R. Kawaguchi,et al.  Mapping the membrane topology and extracellular ligand binding domains of the retinol binding protein receptor. , 2008, Biochemistry.

[195]  J. Plutzky,et al.  Retinoid metabolism and nuclear receptor responses: New insights into coordinated regulation of the PPAR–RXR complex , 2008, FEBS letters.

[196]  Ying Chen,et al.  Inhibition of the visual cycle by A2E through direct interaction with RPE65 and implications in Stargardt disease , 2010, Proceedings of the National Academy of Sciences.

[197]  E. Harrison,et al.  Hydrolysis of retinyl palmitate by enzymes of rat pancreas and liver. Differentiation of bile salt-dependent and bile salt-independent, neutral retinyl ester hydrolases in rat liver. , 1989, The Journal of biological chemistry.

[198]  D. Oprian,et al.  Heterozygous missense mutation in the rhodopsin gene as a cause of congenital stationary night blindness , 1993, Nature Genetics.

[199]  F. Gage,et al.  An essential role for retinoid receptors RARbeta and RXRgamma in long-term potentiation and depression. , 1998, Neuron.

[200]  D. Bok,et al.  Rhodopsin chromophore exchanges among opsin molecules in the dark. , 1983, Investigative ophthalmology & visual science.

[201]  J. Heller Interactions of plasma retinol-binding protein with its receptor. Specific binding of bovine and human retinol-binding protein to pigment epithelium cells from bovine eyes. , 1975, The Journal of biological chemistry.

[202]  J. Bellingham,et al.  Addition of human melanopsin renders mammalian cells photoresponsive , 2005, Nature.

[203]  H. Khorana Rhodopsin, photoreceptor of the rod cell. An emerging pattern for structure and function. , 1992, The Journal of biological chemistry.

[204]  E. Harrison,et al.  Carotenoid transport is decreased and expression of the lipid transporters SR-BI, NPC1L1, and ABCA1 is downregulated in Caco-2 cells treated with ezetimibe. , 2005, The Journal of nutrition.

[205]  G. Mortier,et al.  Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary dysplasia, lung hypoplasia, and mental retardation. , 2007, American journal of human genetics.

[206]  D. Bok,et al.  Retinal Pigment Epithelium-Retinal G Protein Receptor-Opsin Mediates Light-dependent Translocation of All-trans-retinyl Esters for Synthesis of Visual Chromophore in Retinal Pigment Epithelial Cells* , 2008, Journal of Biological Chemistry.

[207]  K. Palczewski,et al.  Effects of long-term administration of 9-cis-retinyl acetate on visual function in mice. , 2009, Investigative ophthalmology & visual science.

[208]  D R Pepperberg,et al.  Retinoids and the Visual Process , 1996, Photochemistry and photobiology.

[209]  A. Ross,et al.  The function of vitamin A in cellular growth and differentiation, and its roles during pregnancy and lactation. , 1994, Advances in experimental medicine and biology.

[210]  R. Hennekam,et al.  Mutations in STRA6 cause a broad spectrum of malformations including anophthalmia, congenital heart defects, diaphragmatic hernia, alveolar capillary dysplasia, lung hypoplasia, and mental retardation. , 2007, American Journal of Human Genetics.

[211]  K. Palczewski,et al.  Diseases caused by defects in the visual cycle: retinoids as potential therapeutic agents. , 2007, Annual review of pharmacology and toxicology.

[212]  J. von Lintig,et al.  The Drosophila class B scavenger receptor NinaD-I is a cell surface receptor mediating carotenoid transport for visual chromophore synthesis. , 2006, Biochemistry.

[213]  M. Max,et al.  Pineal opsin: a nonvisual opsin expressed in chick pineal , 1995, Science.

[214]  P. Gouras,et al.  Correction of the disease phenotype in the mouse model of Stargardt disease by lentiviral gene therapy , 2008, Gene Therapy.

[215]  R. Evans The molecular basis of signaling by vitamin A and its metabolites. , 1994, Harvey lectures.

[216]  P. Dollé,et al.  Retinoic acid in development: towards an integrated view , 2008, Nature Reviews Genetics.

[217]  P. Chambon,et al.  Developmental expression pattern of Stra6, a retinoic acid-responsive gene encoding a new type of membrane protein , 1997, Mechanisms of Development.

[218]  J. Nathans In the eye of the beholder: Visual pigments and inherited variation in human vision , 1994, Cell.

[219]  Jean Bennett,et al.  Mutations in ABCA4 result in accumulation of lipofuscin before slowing of the retinoid cycle: a reappraisal of the human disease sequence. , 2004, Human molecular genetics.

[220]  J. Nathans,et al.  Mechanisms of spectral tuning in the mouse green cone pigment. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[221]  D. Oprian,et al.  Opsin activation as a cause of congenital night blindness , 2003, Nature Neuroscience.

[222]  T. Sakmar,et al.  Interaction of A 2 E with Model Membranes . Implications to the Pathogenesis of Age-related Macular Degeneration , 2002 .

[223]  M. Boulton,et al.  RPE lipofuscin and its role in retinal pathobiology. , 2005, Experimental eye research.

[224]  F. R. Smith,et al.  Vitamin A transport in human vitamin A toxicity. , 1976, The New England journal of medicine.

[225]  M. Maguire,et al.  NinaB Is Essential for Drosophila Vision but Induces Retinal Degeneration in Opsin-deficient Photoreceptors* , 2009, The Journal of Biological Chemistry.

[226]  A. Sommer Vitamin A deficiency, child health, and survival. , 1997, Nutrition.

[227]  R. W. Yost,et al.  Esterification by rat liver microsomes of retinol bound to cellular retinol-binding protein. , 1988, The Journal of biological chemistry.

[228]  R. Molday,et al.  The role of the photoreceptor ABC transporter ABCA4 in lipid transport and Stargardt macular degeneration. , 2009, Biochimica et biophysica acta.

[229]  W. Driever,et al.  RBP4 disrupts vitamin A uptake homeostasis in a STRA6-deficient animal model for Matthew-Wood syndrome. , 2008, Cell metabolism.

[230]  J. Nathans,et al.  Stargardt's ABCR is localized to the disc membrane of retinal rod outer segments , 1997, Nature Genetics.

[231]  A. Chess,et al.  Function of Rhodopsin in Temperature Discrimination in Drosophila , 2011, Science.

[232]  Yiannis Koutalos,et al.  Reduction of all-trans retinal to all-trans retinol in the outer segments of frog and mouse rod photoreceptors. , 2005, Biophysical journal.

[233]  P. Ping,et al.  A Membrane Receptor for Retinol Binding Protein Mediates Cellular Uptake of Vitamin A , 2007, Science.

[234]  G. Fain Dark adaptation. , 2001, Progress in brain research.

[235]  Richard G. W. Anderson,et al.  Murine SR-BI, a High Density Lipoprotein Receptor That Mediates Selective Lipid Uptake, Is N-Glycosylated and Fatty Acylated and Colocalizes with Plasma Membrane Caveolae* , 1997, The Journal of Biological Chemistry.

[236]  W. Blaner,et al.  Pathways of vitamin A delivery to the embryo: insights from a new tunable model of embryonic vitamin A deficiency. , 2005, Endocrinology.

[237]  D. Oprian,et al.  Spectral tuning in the human blue cone pigment. , 1999, Biochemistry.

[238]  J. Smith,et al.  Metabolism of retinol-binding protein and vitamin A during hypervitaminosis A in the rat. , 1975, Journal of lipid research.

[239]  T. Sakmar,et al.  Colour tuning mechanisms of visual pigments. , 1999, Novartis Foundation symposium.

[240]  K. Nakanishi,et al.  A2E, a fluorophore of RPE lipofuscin, can destabilize membrane. , 2006, Advances in experimental medicine and biology.

[241]  L. Wheless,et al.  Effective and sustained delivery of hydrophobic retinoids to photoreceptors. , 2010, Investigative ophthalmology & visual science.

[242]  E. Picard,et al.  Pulmonary hypoplasia–diaphragmatic hernia–anophthalmia–cardiac defect (PDAC) syndrome due to STRA6 mutations—What are the minimal criteria? , 2009, American journal of medical genetics. Part A.

[243]  G. Fishman,et al.  Delayed rod dark adaptation in patients with Stargardt's disease. , 1991, Ophthalmology.

[244]  A. Sommer Vitamin A Deficiency , 2001 .

[245]  J. Lupski,et al.  A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Starqardt macular dystrophy , 1997, Nature Genetics.

[246]  P. Gouras,et al.  Muscle Expression of Human Retinol-binding Protein (RBP) , 2002, The Journal of Biological Chemistry.

[247]  Vladimir J. Kefalov,et al.  Intra-Retinal Visual Cycle Required for Rapid and Complete Cone Dark Adaptation , 2009, Nature Neuroscience.