Blue light regenerates functional visual pigments in mammals through a retinyl-phospholipid intermediate

The light absorbing chromophore in opsin visual pigments is the protonated Schiff base of 11-cis-retinaldehyde (11cRAL). Absorption of a photon isomerizes 11cRAL to all-trans-retinaldehyde (atRAL), briefly activating the pigment before it dissociates. Light sensitivity is restored when apo-opsin combines with another 11cRAL to form a new visual pigment. Conversion of atRAL to 11cRAL is carried out by enzyme pathways in neighboring cells. Here we show that blue (450-nm) light converts atRAL specifically to 11cRAL through a retinyl-phospholipid intermediate in photoreceptor membranes. The quantum efficiency of this photoconversion is similar to rhodopsin. Photoreceptor membranes synthesize 11cRAL chromophore faster under blue light than in darkness. Live mice regenerate rhodopsin more rapidly in blue light. Finally, whole retinas and isolated cone cells show increased photosensitivity following exposure to blue light. These results indicate that light contributes to visual-pigment renewal in mammalian rods and cones through a non-enzymatic process involving retinyl-phospholipids.It is currently thought that visual pigments in vertebrate photoreceptors are regenerated exclusively through enzymatic cycles. Here the authors show that mammalian photoreceptors also regenerate opsin pigments in light through photoisomerization of N-ret-PE (N-retinylidene-phosphatidylethanolamine.

[1]  G. Aguirre,et al.  Unique topographic separation of two spectral classes of cones in the mouse retina , 1992, The Journal of comparative neurology.

[2]  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.

[3]  J. Kaylor,et al.  Identification of the 11-cis-specific retinyl-ester synthase in retinal Müller cells as multifunctional O-acyltransferase (MFAT) , 2014, Proceedings of the National Academy of Sciences.

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

[5]  Edward A. Boettner,et al.  Transmission of the Ocular Media , 1962 .

[6]  Y. Fukada,et al.  PHOTOSENSITIVITIES OF IODOPSIN AND RHODOPSINS , 1992, Photochemistry and photobiology.

[7]  R. Sidman,et al.  Phototransduction in transgenic mice after targeted deletion of the rod transducin alpha -subunit. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[8]  S. Hosier,et al.  Purification of PDE6 isozymes from mammalian retina. , 2005, Methods in molecular biology.

[9]  R. Somers,et al.  Possible involvement of retinylidene phospholipid in photoisomerization of all-trans-retinal to 11-cis-retinal. , 1974, The Journal of biological chemistry.

[10]  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.

[11]  Y. Koutalos,et al.  Vertebrate Photoreceptors , 2001, Progress in Retinal and Eye Research.

[12]  Steven Nusinowitz,et al.  Identification of DES1 as a Vitamin A Isomerase in Müller Glial Cells of the Retina , 2012, Nature chemical biology.

[13]  R. P. Poincelot,et al.  Lipid to Protein Chromophore Transfer in the Photolysis of Visual Pigments , 1969, Nature.

[14]  E. MacNichol,et al.  Visual pigment bleaching in isolated salamander retinal cones. Microspectrophotometry and light adaptation , 1993, The Journal of general physiology.

[15]  C. Grimm,et al.  Blue light's effects on rhodopsin: photoreversal of bleaching in living rat eyes. , 2000, Investigative ophthalmology & visual science.

[16]  G. Wald,et al.  THE MOLAR EXTINCTION OF RHODOPSIN , 1953, The Journal of general physiology.

[17]  W. J. Dyer,et al.  A rapid method of total lipid extraction and purification. , 1959, Canadian journal of biochemistry and physiology.

[18]  F. I. Hárosi,et al.  Solubility of retinoids in water. , 1991, Archives of biochemistry and biophysics.

[19]  Ting Wang,et al.  Retinal release from opsin in molecular dynamics simulations , 2011, Journal of molecular recognition : JMR.

[20]  M. Jiang,et al.  Cytoplasmic retinal localization of an evolutionary homolog of the visual pigments. , 1994, Experimental eye research.

[21]  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.

[22]  G. Groenendijk,et al.  Dark isomerization of retinals in the presence of phosphatidylethanolamine. , 2005, European journal of biochemistry.

[23]  W. Hubbell,et al.  The intrinsic pKa values for phosphatidylserine and phosphatidylethanolamine in phosphatidylcholine host bilayers. , 1986, Biophysical journal.

[24]  M J Tauber,et al.  Wavelength dependent cis-trans isomerization in vision. , 2001, Biochemistry.

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

[26]  K. Hofmann,et al.  Photoregeneration of bovine rhodopsin from its signaling state. , 1995, Biochemistry.

[27]  J. C. Saari,et al.  Photochemistry and stereoselectivity of cellular retinaldehyde-binding protein from bovine retina. , 1987, The Journal of biological chemistry.

[28]  J. Nickerson,et al.  A History of the Classical Visual Cycle. , 2015, Progress in molecular biology and translational science.

[29]  R. Molday,et al.  ABCA4 is an N-retinylidene-phosphatidylethanolamine and phosphatidylethanolamine importer , 2012, Nature Communications.

[30]  F. Cañada,et al.  Membranes as the energy source in the endergonic transformation of vitamin A to 11-cis-retinol. , 1989, Science.

[31]  Vladimir J. Kefalov,et al.  The Cone-specific visual cycle , 2011, Progress in Retinal and Eye Research.

[32]  R. Sidman,et al.  Phototransduction in transgenic mice after targeted deletion of the rod transducin α-subunit , 2000 .

[33]  T. Williams,et al.  Photoreversal of Rhodopsin Bleaching , 1964, The Journal of general physiology.

[34]  M. Lavail,et al.  Rods and cones in the mouse retina. I. Structural analysis using light and electron microscopy , 1979, The Journal of comparative neurology.

[35]  T Michael Redmond,et al.  RPE65, Visual Cycle Retinol Isomerase, Is Not Inherently 11-cis-specific , 2009, The Journal of Biological Chemistry.

[36]  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.

[37]  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.

[38]  Kimbel Rl,et al.  Chromophore transfer from lipid to protein in bovine rhodopsin , 1970 .

[39]  M. Cornwall,et al.  Bleached pigment activates transduction in isolated rods of the salamander retina. , 1994, The Journal of physiology.

[40]  E. Shelton,et al.  Assessment of physiological integrity of sonicated retinal rod membranes. , 1974, Journal of supramolecular structure.

[41]  Oliver P. Ernst,et al.  A Ligand Channel through the G Protein Coupled Receptor Opsin , 2009, PloS one.

[42]  J. Vance.  Phospholipid Synthesis and Transport in Mammalian Cells , 2015, Traffic.

[43]  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.

[44]  G. Fain,et al.  Early receptor current of wild‐type and transducin knockout mice: photosensitivity and light‐induced Ca2+ release , 2004, The Journal of physiology.

[45]  E. Pugh,et al.  Photoreceptors of Nrl −/− Mice Coexpress Functional S- and M-cone Opsins Having Distinct Inactivation Mechanisms , 2005, The Journal of general physiology.

[46]  G. Fain,et al.  Opsin activation of transduction in the rods of dark‐reared Rpe65 knockout mice , 2005, The Journal of physiology.

[47]  G. Fain,et al.  Equivalence of background and bleaching desensitization in isolated rod photoreceptors of the larval tiger salamander , 1996, The Journal of general physiology.

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

[49]  H. Dartnall.  The photosensitivities of visual pigments in the presence of hydroxylamine. , 1968, Vision research.

[50]  Edward N. Pugh,et al.  Physiological Features of the S- and M-cone Photoreceptors of Wild-type Mice from Single-cell Recordings , 2006, The Journal of general physiology.

[51]  H. Kandori,et al.  Structural changes in lumirhodopsin and metarhodopsin I studied by their photoreactions at 77 K. , 2003, Biochemistry.

[52]  M. Woodruff,et al.  Bleaching of mouse rods: microspectrophotometry and suction‐electrode recording , 2012, The Journal of physiology.

[53]  R. E. Anderson,et al.  Phospholipids of bovine outer segments. , 1970, Biochemistry.

[54]  C. Montell.  Drosophila visual transduction , 2012, Trends in Neurosciences.