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The Visual Cycle in the Inner Retina of Chicken and the Involvement of Retinal G-Protein-Coupled Receptor (RGR)

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Abstract

The vertebrate retina contains typical photoreceptor (PR) cones and rods responsible for day/night vision, respectively, and intrinsically photosensitive retinal ganglion cells (ipRGCs) involved in the regulation of non-image-forming tasks. Rhodopsin/cone opsin photopigments in visual PRs or melanopsin (Opn4) in ipRGCs utilizes retinaldehyde as a chromophore. The retinoid regeneration process denominated as “visual cycle” involves the retinal pigment epithelium (RPE) or Müller glial cells. Opn4, on the contrary, has been characterized as a bi/tristable photopigment, in which a photon of one wavelength isomerizes 11-cis to all-trans retinal (Ral), with a second photon re-isomerizing it back. However, it is unknown how the chromophore is further metabolized in the inner retina. Nor is it yet clear whether an alternative secondary cycle occurs involving players such as the retinal G-protein-coupled receptor (RGR), a putative photoisomerase of unidentified inner retinal activity. Here, we investigated the role of RGR in retinoid photoisomerization in Opn4x (Xenopus ortholog) (+) RGC primary cultures free of RPE and other cells from chicken embryonic retinas. Opn4x (+) RGCs display significant photic responses by calcium fluorescent imaging and photoisomerize exogenous all-trans to 11-cis Ral and other retinoids. RGR was found to be expressed in developing retina and in primary cultures; when its expression was knocked down, the levels of 11-cis, all-trans Ral, and all-trans retinol in cultures exposed to light were significantly higher and those in all-trans retinyl esters lower than in dark controls. The results support a novel role for RGR in ipRGCs to modulate retinaldehyde levels in light, keeping the balance of inner retinal retinoid pools.

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References

  1. Berson DM, Dunn FA, Takao M (2002) Phototransduction by retinal ganglion cells that set the circadian clock. Science 295(5557):1070–1073. doi:10.1126/science.1067262

    Article  CAS  PubMed  Google Scholar 

  2. Hattar S, Liao HW, Takao M, Berson DM, Yau KW (2002) Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity. Science 295(5557):1065–1070. doi:10.1126/science.1069609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Provencio I, Rodriguez IR, Jiang G, Hayes WP, Moreira EF, Rollag MD (2000) A novel human opsin in the inner retina. J Neurosci: Off J Soc Neurosci 20(2):600–605

    CAS  Google Scholar 

  4. Panda S, Sato TK, Castrucci AM, Rollag MD, DeGrip WJ, Hogenesch JB, Provencio I, Kay SA (2002) Melanopsin (Opn4) requirement for normal light-induced circadian phase shifting. Science 298(5601):2213–2216. doi:10.1126/science.1076848

    Article  CAS  PubMed  Google Scholar 

  5. Panda S, Provencio I, Tu DC, Pires SS, Rollag MD, Castrucci AM, Pletcher MT, Sato TK et al (2003) Melanopsin is required for non-image-forming photic responses in blind mice. Science 301(5632):525–527. doi:10.1126/science.1086179

    Article  CAS  PubMed  Google Scholar 

  6. Lucas RJ, Hattar S, Takao M, Berson DM, Foster RG, Yau KW (2003) Diminished pupillary light reflex at high irradiances in melanopsin-knockout mice. Science 299(5604):245–247. doi:10.1126/science.1077293

    Article  CAS  PubMed  Google Scholar 

  7. Schmidt TM, Alam NM, Chen S, Kofuji P, Li W, Prusky GT, Hattar S (2014) A role for melanopsin in alpha retinal ganglion cells and contrast detection. Neuron 82(4):781–788. doi:10.1016/j.neuron.2014.03.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Allen AE, Storchi R, Martial FP, Petersen RS, Montemurro MA, Brown TM, Lucas RJ (2014) Melanopsin-driven light adaptation in mouse vision. Curr Biol: CB 24(21):2481–2490. doi:10.1016/j.cub.2014.09.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Guido ME, Garbarino-Pico E, Contin MA, Valdez DJ, Nieto PS, Verra DM, Acosta-Rodriguez VA, de Zavalia N et al (2010) Inner retinal circadian clocks and non-visual photoreceptors: novel players in the circadian system. Prog Neurobiol 92(4):484–504. doi:10.1016/j.pneurobio.2010.08.005

    Article  PubMed  Google Scholar 

  10. Wald G (1968) The molecular basis of visual excitation. Nature 219(5156):800–807

    Article  CAS  PubMed  Google Scholar 

  11. Mata NL, Radu RA, Clemmons RC, Travis GH (2002) Isomerization and oxidation of vitamin a in cone-dominant retinas: a novel pathway for visual-pigment regeneration in daylight. Neuron 36(1):69–80

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Diaz NM, Morera LP, Guido ME (2016) Melanopsin and the non-visual photochemistry in the inner retina of vertebrates. Photochem Photobiol 92:29–44. doi:10.1111/php.12545

    Article  CAS  PubMed  Google Scholar 

  13. Matsuyama T, Yamashita T, Imamoto Y, Shichida Y (2012) Photochemical properties of mammalian melanopsin. Biochemistry 51(27):5454–5462. doi:10.1021/bi3004999

    Article  CAS  PubMed  Google Scholar 

  14. Emanuel AJ, Do MT (2015) Melanopsin tristability for sustained and broadband phototransduction. Neuron 85(5):1043–1055. doi:10.1016/j.neuron.2015.02.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Qiu X, Kumbalasiri T, Carlson SM, Wong KY, Krishna V, Provencio I, Berson DM (2005) Induction of photosensitivity by heterologous expression of melanopsin. Nature 433(7027):745–749. doi:10.1038/nature03345

    Article  CAS  PubMed  Google Scholar 

  16. Melyan Z, Tarttelin EE, Bellingham J, Lucas RJ, Hankins MW (2005) Addition of human melanopsin renders mammalian cells photoresponsive. Nature 433(7027):741–745. doi:10.1038/nature03344

    Article  CAS  PubMed  Google Scholar 

  17. Panda S, Nayak SK, Campo B, Walker JR, Hogenesch JB, Jegla T (2005) Illumination of the melanopsin signaling pathway. Science 307(5709):600–604. doi:10.1126/science.1105121

    Article  CAS  PubMed  Google Scholar 

  18. Tu DC, Zhang D, Demas J, Slutsky EB, Provencio I, Holy TE, Van Gelder RN (2005) Physiologic diversity and development of intrinsically photosensitive retinal ganglion cells. Neuron 48(6):987–999. doi:10.1016/j.neuron.2005.09.031

    Article  CAS  PubMed  Google Scholar 

  19. Koyanagi M, Kubokawa K, Tsukamoto H, Shichida Y, Terakita A (2005) Cephalochordate melanopsin: evolutionary linkage between invertebrate visual cells and vertebrate photosensitive retinal ganglion cells. Curr Biol: CB 15(11):1065–1069. doi:10.1016/j.cub.2005.04.063

    Article  CAS  PubMed  Google Scholar 

  20. Wang X, Wang T, Jiao Y, von Lintig J, Montell C (2010) Requirement for an enzymatic visual cycle in Drosophila. Curr Biol: CB 20(2):93–102. doi:10.1016/j.cub.2009.12.022

    Article  CAS  PubMed  Google Scholar 

  21. Wang X, Wang T, Ni JD, von Lintig J, Montell C (2012) The Drosophila visual cycle and de novo chromophore synthesis depends on rdhB. J Neurosci: Off J Soc Neurosci 32(10):3485–3491. doi:10.1523/JNEUROSCI.5350-11.2012

    Article  CAS  Google Scholar 

  22. Pandey S, Blanks JC, Spee C, Jiang M, Fong HK (1994) Cytoplasmic retinal localization of an evolutionary homolog of the visual pigments. Exp Eye Res 58(5):605–613. doi:10.1006/exer.1994.1055

    Article  CAS  PubMed  Google Scholar 

  23. Hao W, Fong HK (1996) Blue and ultraviolet light-absorbing opsin from the retinal pigment epithelium. Biochemistry 35(20):6251–6256. doi:10.1021/bi952420k

    Article  CAS  PubMed  Google Scholar 

  24. Shen D, Jiang M, Hao W, Tao L, Salazar M, Fong HK (1994) A human opsin-related gene that encodes a retinaldehyde-binding protein. Biochemistry 33(44):13117–13125

    Article  CAS  PubMed  Google Scholar 

  25. Hao W, Fong HK (1999) The endogenous chromophore of retinal G protein-coupled receptor opsin from the pigment epithelium. J Biol Chem 274(10):6085–6090

    Article  CAS  PubMed  Google Scholar 

  26. Chen P, Hao W, Rife L, Wang XP, Shen D, Chen J, Ogden T, Van Boemel GB et al (2001) A photic visual cycle of rhodopsin regeneration is dependent on Rgr. Nat Genet 28(3):256–260. doi:10.1038/90089

    Article  CAS  PubMed  Google Scholar 

  27. Chen P, Lee TD, Fong HK (2001) Interaction of 11-cis-retinol dehydrogenase with the chromophore of retinal G protein-coupled receptor opsin. J Biol Chem 276(24):21098–21104. doi:10.1074/jbc.M010441200

    Article  CAS  PubMed  Google Scholar 

  28. Maeda T, Van Hooser JP, Driessen CA, Filipek S, Janssen JJ, Palczewski K (2003) Evaluation of the role of the retinal G protein-coupled receptor (RGR) in the vertebrate retina in vivo. J Neurochem 85(4):944–956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wenzel A, Oberhauser V, Pugh EN Jr, Lamb TD, Grimm C, Samardzija M, Fahl E, Seeliger MW et al (2005) The retinal G protein-coupled receptor (RGR) enhances isomerohydrolase activity independent of light. J Biol Chem 280(33):29874–29884. doi:10.1074/jbc.M503603200

    Article  CAS  PubMed  Google Scholar 

  30. Radu RA, Hu J, Peng J, Bok D, Mata NL, Travis GH (2008) 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. J Biol Chem 283(28):19730–19738. doi:10.1074/jbc.M801288200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Verra DM, Contin MA, Hicks D, Guido ME (2011) Early onset and differential temporospatial expression of melanopsin isoforms in the developing chicken retina. Invest Ophthalmol Vis Sci 52(8):5111–5120. doi:10.1167/iovs.11-75301

    Article  CAS  PubMed  Google Scholar 

  32. Diaz NM, Morera LP, Verra DM, Contin MA, Guido ME (2014) Early appearance of nonvisual and circadian markers in the developing inner retinal cells of chicken. BioMed Res Int 2014:646847. doi:10.1155/2014/646847

    Article  PubMed  PubMed Central  Google Scholar 

  33. Morera LP, Diaz NM, Guido ME (2012) A novel method to prepare highly enriched primary cultures of chicken retinal horizontal cells. Exp Eye Res 101:44–48. doi:10.1016/j.exer.2012.05.010

    Article  CAS  PubMed  Google Scholar 

  34. Contin MA, Verra DM, Salvador G, Ilincheta M, Giusto NM, Guido ME (2010) Light activation of the phosphoinositide cycle in intrinsically photosensitive chicken retinal ganglion cells. Invest Ophthalmol Vis Sci 51(11):5491–5498. doi:10.1167/iovs.10-5643

    Article  PubMed  Google Scholar 

  35. Contin MA, Verra DM, Guido ME (2006) An invertebrate-like phototransduction cascade mediates light detection in the chicken retinal ganglion cells. FASEB J: Off Publ Fed Am Soc Exp Biol 20(14):2648–2650. doi:10.1096/fj.06-6133fje

    Article  CAS  Google Scholar 

  36. Groenendijk GW, De Grip WJ, Daemen FJ (1980) Quantitative determination of retinals with complete retention of their geometric configuration. Biochim Biophys Acta 617(3):430–438

    Article  CAS  PubMed  Google Scholar 

  37. Garwin GG, Saari JC (2000) High-performance liquid chromatography analysis of visual cycle retinoids. Methods Enzymol 316:313–324

    Article  CAS  PubMed  Google Scholar 

  38. Lin MY, Kochounian H, Moore RE, Lee TD, Rao N, Fong HK (2007) Deposition of exon-skipping splice isoform of human retinal G protein-coupled receptor from retinal pigment epithelium into Bruch’s membrane. Mol Vis 13:1203–1214

    CAS  PubMed  Google Scholar 

  39. Lhor M, Salesse C (2014) Retinol dehydrogenases: membrane-bound enzymes for the visual function. Biochem Cell Biol = Biochim Biol Cell 92(6):510–523. doi:10.1139/bcb-2014-0082

    Article  CAS  Google Scholar 

  40. Batten ML, Imanishi Y, Maeda T, Tu DC, Moise AR, Bronson D, Possin D, Van Gelder RN et al (2004) Lecithin-retinol acyltransferase is essential for accumulation of all-trans-retinyl esters in the eye and in the liver. J Biol Chem 279(11):10422–10432. doi:10.1074/jbc.M312410200

    Article  CAS  PubMed  Google Scholar 

  41. Kiser PD, Golczak M, Palczewski K (2014) Chemistry of the retinoid (visual) cycle. Chem Rev 114(1):194–232. doi:10.1021/cr400107q

    Article  CAS  PubMed  Google Scholar 

  42. Kaylor JJ, Yuan Q, Cook J, Sarfare S, Makshanoff J, Miu A, Kim A, Kim P et al (2013) Identification of DES1 as a vitamin A isomerase in Müller glial cells of the retina. Nat Chem Biol 9(1):30–36. doi:10.1038/nchembio.1114

    Article  CAS  PubMed  Google Scholar 

  43. Kaylor J, Alfaro M, Ishwar A, Sailey C, Sawyer J, Zarate YA (2014) Molecular and cytogenetic evaluation of a patient with ring chromosome 13 and discordant results. Cytogenet Genome Res 144(2):104–108. doi:10.1159/000368649

    Article  PubMed  Google Scholar 

  44. Kaylor JJ, Radu RA, Bischoff N, Makshanoff J, Hu J, Lloyd M, Eddington S, Bianconi T et al (2015) Diacylglycerol O-acyltransferase type-1 synthesizes retinyl esters in the retina and retinal pigment epithelium. PLoS One 10(5):e0125921. doi:10.1371/journal.pone.0125921

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work has been supported by the Agencia Nacional de Promoción Científica y Técnica (FONCyT, PICT 2010 No. 647 and PICT 2013 No. 021), Consejo Nacional de Investigaciones Científicas y Tecnológicas de la República Argentina (CONICET; PIP 2011 and 2014), and Secretaría de Ciencia y Tecnología de la Universidad Nacional de Córdoba (SeCyT-UNC). The authors are grateful to Dr. Andrew Tsin and Mrs. Brandy Betts for their excellent assistance in retinoid purification and identification in control retinal samples, and for the gift of the RGR antibody.

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  1. CIQUIBIC—Departamento de Química Biológica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba-CONICET, Ciudad Universitaria, 5000, Córdoba, Argentina

    Nicolás M. Díaz, Luis P. Morera & Mario E. Guido

  2. Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba (UNC), 5000, Córdoba, Argentina

    Tomas Tempesti

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  1. Nicolás M. Díaz
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Correspondence to Mario E. Guido.

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Díaz, N.M., Morera, L.P., Tempesti, T. et al. The Visual Cycle in the Inner Retina of Chicken and the Involvement of Retinal G-Protein-Coupled Receptor (RGR). Mol Neurobiol 54, 2507–2517 (2017). https://doi.org/10.1007/s12035-016-9830-5

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