The retina visual cycle is driven by cis retinol oxidation in the outer segments of cones
Open accessAbstract
Vertebrate rod and cone photoreceptors require continuous supply of chromophore for regenerating their visual pigments after photoactivation. Cones, which mediate our daytime vision, demand a particularly rapid supply of 11-cis retinal chromophore in order to maintain their function in bright light. An important contribution to this process is thought to be the chromophore precursor 11-cis retinol, which is supplied to cones from Müller cells in the retina and subsequently oxidized to 11-cis retinal as part of the retina visual cycle. However, the molecular identity of the cis retinol oxidase in cones remains unclear. Here, as a first step in characterizing this enzymatic reaction, we sought to determine the subcellular localization of this activity in salamander red cones. We found that the onset of dark adaptation of isolated salamander red cones was substantially faster when exposing directly their outer vs. their inner segment to 9-cis retinol, an analogue of 11-cis retinol. In contrast, this difference was not observed when treating the outer vs. inner segment with 9-cis retinal, a chromophore analogue which can directly support pigment regeneration. These results suggest, surprisingly, that the cis-retinol oxidation occurs in the outer segments of cone photoreceptors. Confirming this notion, pigment regeneration with exogenously added 9-cis retinol was directly observed in the truncated outer segments of cones, but not in rods. We conclude that the enzymatic machinery required for the oxidation of recycled cis retinol as part of the retina visual cycle is present in the outer segments of cones.
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Because rods depend entirely on 11-cis-retinal and cones can also utilize 11-cis-retinol, competition for this visual cycle product is avoided.
“As rods depend entirely on 11-cis-retinal and cones can also utilize 11-cis-retinol, the competition for this visual cycle product is avoided [52,63,65,66].”
From The Role of Vitamin A in Retinal Diseases (2022) · cites this paper as [65]
The Introduction (page unavailable) says Müller cells supply 11-cis-retinol to cones, which can oxidize it, and describes that activity as cone-specific. The Results (page unavailable) report that salamander rods could not use a cis-retinol analogue for pigment regeneration. But the paper does not establish that competition is avoided; the Introduction also says the RPE supplies 11-cis-retinal to both rods and cones. (LLM, conf=0.85)
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References 45 · Cited by 25
Research works printed but not linked: 38
- Ala-Laurila P Cornwall MC Crouch RK Kono M 2009 The action of 11-cis-retinol on cone opsins and intact cone photoreceptors Journal of Biological Chemistry 284 16492 16500 19386593 PMC2713570
- Bok D Ong DE Chytil F 1984 Immunocytochemical localization of cellular retinol binding protein in the rat retina Investigative Ophthalmology & Visual Science 25 877 883 6746230
- Collery R McLoughlin S Vendrell V Finnegan J Crabb JW Saari JC Kennedy BN 2008 Duplication and divergence of zebrafish CRALBP genes uncovers novel role for RPE- and Muller-CRALBP in cone vision Investigative Ophthalmology & Visual Science 49 3812 3820 18502992
- Ebrey T Koutalos Y 2001 Vertebrate photoreceptors Progress in Retinal and Eye Research 20 49 94 11070368
- Frederiksen R Boyer NP Nickle B Chakrabarti KS Koutalos Y Crouch RK Oprian D Cornwall MC 2012 Low aqueous solubility of 11-cis-retinal limits the rate of pigment formation and dark adaptation in salamander rods Journal of General Physiology 139 493 505 22641642 PMC3362518
- Garlipp MA Gonzalez-Fernandez F 2013 Cone outer segment and Muller microvilli pericellular matrices provide binding domains for interphotoreceptor retinoid-binding protein (IRBP) Exp. Eye Res 113 192 202 23470504
- Haeseleer F Jang GF Imanishi Y Driessen CA Matsumura M Nelson PS Palczewski K 2002 Dual-substrate specificity short chain retinol dehydrogenases from the vertebrate retina Journal of Biological Chemistry 277 45537 45546 12226107 PMC1435693
- Harosi FI 1975 Absorption spectra and linear dichroism of some amphibian photoreceptors Journal of General Physiology 66 357 382 808586 PMC2226208
- Imamoto Y Shichida Y 2014 Cone visual pigments Biochimica et Biophysica Acta 1837 664 673 24021171
- Insinna C Daniele LL Davis JA Larsen DD Kuemmel C Wang J Nikonov SS Knox BE Pugh EN Jr 2012 An S-opsin knock-in mouse (F81Y) reveals a role for the native ligand 11-cis-retinal in cone opsin biosynthesis Journal of Neuroscience 32 8094 8104 22674284 PMC3381355
- Jones GJ Fein A MacNichol EF Jr Cornwall MC 1993 Visual pigment bleaching in isolated salamander retinal cones. Microspectrophotometry and light adaptation Journal of General Physiology 102 483 502 8245820 PMC2229157
- Kanan Y Kasus-Jacobi A Moiseyev G Sawyer K Ma JX Al-Ubaidi MR 2008 Retinoid processing in cone and Muller cell lines Experimental Eye Research 86 344 354 18163989 PMC2947831
- Kawamura S Murakami M 1989 Regulation of cGMP levels by guanylate cyclase in truncated frog rod outer segments Journal of General Physiology 94 649 668 2575652 PMC2228963
- Kaylor JJ Cook JD Makshanoff J Bischoff N Yong J Travis GH 2014 Identification of the 11-cis-specific retinyl-ester synthase in retinal Muller cells as multifunctional O-acyltransferase (MFAT) Proceedings of the National Academy of Sciences of the United States of America 111 7302 7307 24799687 PMC4034218
- Kaylor JJ Yuan Q Cook J Sarfare S Makshanoff J Miu A Kim A Kim P Habib S Roybal CN Xu T Nusinowitz S Travis GH 2013 Identification of DES1 as a vitamin A isomerase in Muller glial cells of the retina Nature Chemical Biology 9 30 36 23143414 PMC3522777
- Kefalov VJ Crouch RK Cornwall MC 2001 Role of noncovalent binding of 11-cis-retinal to opsin in dark adaptation of rod and cone photoreceptors Neuron 29 749 755 11301033
- Kefalov VJ Estevez ME Kono M Goletz PW Crouch RK Cornwall MC Yau KW 2005 Breaking the covalent bond—A pigment property that contributes to desensitization in cones Neuron 46 879 890 15953417 PMC2885911
- Kolesnikov AV Maeda A Tang PH Imanishi Y Palczewski K Kefalov VJ 2015 Retinol dehydrogenase 8 and ATP-binding cassette transporter 4 modulate dark adaptation of M-cones in mammalian retina Journal of Physiology 593 4923 4941 26350353 PMC4650407
- Kolesnikov AV Tang PH Parker RO Crouch RK Kefalov VJ 2011 The mammalian cone visual cycle promotes rapid M/L-cone pigment regeneration independently of the interphotoreceptor retinoid-binding protein Journal of Neuroscience 31 7900 7909 21613504 PMC3108150
- Koutalos Y Cornwall MC 2010 Microfluorometric measurement of the formation of all-trans-retinol in the outer segments of single isolated vertebrate photoreceptors Methods in Molecular Biology 652 129 147 20552426 PMC3010976
- Maeda A Maeda T Imanishi Y Kuksa V Alekseev A Bronson JD Zhang H Zhu L Sun W Saperstein DA Rieke F Baehr W Palczewski K 2005 Role of photoreceptor-specific retinol dehydrogenase in the retinoid cycle in vivo Journal of Biological Chemistry 280 18822 18832 15755727 PMC1283069
- Makino CL Dodd RL 1996 Multiple visual pigments in a photoreceptor of the salamander retina Journal of General Physiology 108 27 34 8817382 PMC2229295
- Makino CL Groesbeek M Lugtenburg J Baylor DA 1999 Spectral tuning in salamander visual pigments studied with dihydroretinal chromophores Biophysical Journal 77 1024 1035 10423447 PMC1300393
- 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 69 80 12367507 PMC2851622
- Miyazono S Shimauchi-Matsukawa Y Tachibanaki S Kawamura S 2008 Highly efficient retinal metabolism in cones Proceedings of the National Academy of Sciences of the United States of America 105 16051 16056 18836074 PMC2572916
- Rattner A Smallwood PM Nathans J 2000 Identifi cation and characterization of all-trans-retinol dehydrogenase from photoreceptor outer segments, the visual cycle enzyme that reduces all-trans-retinal to all-trans-retinol Journal of Biological Chemistry 275 11034 11043 10753906
- Saari JC 2012 Vitamin A metabolism in rod and cone visual cycles Annual Review of Nutrition 32 125 145 22809103
- Sarantis M Mobbs P 1992 The spatial relationship between Muller cell processes and the photoreceptor output synapse Brain Research 584 299 304 1325248
- Sato S Fukagawa T Tachibanaki S Yamano Y Wada A Kawamura S 2013 Substrate specificity and subcellular localization of the aldehyde-alcohol redox-coupling reaction in carp cones Journal of Biological Chemistry 288 36589 36597 24217249 PMC3868771
- Sato S Kefalov VJ 2016 cis Retinol oxidation regulates photoreceptor access to the retina visual cycle and cone pigment regeneration Journal of Physiology 594 6753 6765 27385534 PMC5108915
- Sato S Miyazono S Tachibanaki S Kawamura S 2015 RDH13L, an enzyme responsible for the aldehyde-alcohol redox coupling reaction (AL–OL coupling reaction) to supply 11-cis retinal in the carp cone retinoid cycle Journal of Biological Chemistry 290 2983 2992 25533474 PMC4317047
- Sherry DM Bui DD Degrip WJ 1998 Identification and distribution of photoreceptor subtypes in the neotenic tiger salamander retina Visual Neuroscience 15 1175 1187 9839981
- Takemoto N Tachibanaki S Kawamura S 2009 High cGMP synthetic activity in carp cones Proceedings of the National Academy of Sciences of the United States of America 106 11788 11793 19556550 PMC2710672
- Tang PH Wheless L Crouch RK 2011b Regeneration of photopigment is enhanced in mouse cone photoreceptors expressing RPE65 protein Journal of Neuroscience 31 10403 10411 21753017 PMC3153911
- Wang JS Kefalov VJ 2011 The cone-specific visual cycle Progress in Retinal and Eye Research 30 115 128 21111842 PMC3073571
- Wang JS Nymark S Frederiksen R Estevez ME Shen SQ Corbo JC Cornwall MC Kefalov VJ 2014 Chromophore supply rate-limits mammalian photoreceptor dark adaptation Journal of Neuroscience 34 11212 11221 25143602 PMC4138333
- Wright CB Redmond TM Nickerson JM 2015 A history of the classical visual cycle Progress in Molecular Biology and Translational Science 134 433 448 26310169
- Xue Y Shen SQ Jui J Rupp AC Byrne LC Hattar S Flannery JG Corbo JC Kefalov VJ 2015 CRALBP supports the mammalian retinal visual cycle and cone vision Journal of Clinical Investigation 125 727 738 25607845 PMC4319437
- Authors
- SATO, S., FREDERIKSEN, R., CORNWALL, M. C., & KEFALOV, V. J.
- Affiliations
- Washington University in St. Louis (US)
- Boston University (US)
- Corresponding author
- KEFALOV, VLADIMIR J.
- Venue
- Visual Neuroscience
- Publisher
- Maximum Academic Press
- Published
- 2017
- Volume
- 34
- Pages
- E004-E004
- ISSN
- 0952-5238 (ISSN-L)
- 1469-8714
- PMC
- PMC5534460
- OpenAlex
- W2588771727
- Cited by
- 25
- References
- 45
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 4 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 4 · 2019: 1 · 2018: 2 · 2017: 3
- FWCI
- 1.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Visual Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Research to Prevent Blindness (EY002687)
- Medical University of South Carolina
- University of South Carolina
- National Institutes of Health (EY002687)
- National Eye Institute (EY025696, P30EY002687, EY001157, R01EY025696, R01EY019312, R01EY001157, EY019312, EY002687, T32EY013360)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Photoreceptor and optogenetics research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- 11-cis-retinol, 11-cis-retinal, cone photoreceptors, outer segment, dark adaptation, Müller cells, 9-cis-retinal, subcellular localization, rod photoreceptors
- MeSH terms
- Ambystoma, Animals, Dark Adaptation, Diterpenes, Oxidation-Reduction, Photic Stimulation, Retinal Pigments, Retinaldehyde, Vision, Ocular, Vitamin A, Microspectrophotometry, Retinal Cone Photoreceptor Cells, Retinal Photoreceptor Cell Outer Segment
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