A photic visual cycle of rhodopsin regeneration is dependent on Rgr

Chen, Pu; Hao, Wenshan; Rife, Lawrence; Wang, Xiao Peng; Shen, Daiwei; Chen, Jeannie; Ogden, Thomas E.; Boemel, Gretchen B. Van; Wu, Lanyin; Yang, Minji; Fong, Henry K. W.

doi:10.1038/90089

Cited by 167 publications

(148 citation statements)

References 21 publications

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“…First, due to loss of Ϸ70% of the retinal thickness in rd͞rd and rdta mice, the ipRGCs may be physically closer to the RPE and thus retinoid stores. Small amounts of retinal are recycled in rpe65 Ϫ/Ϫ mice, possibly through a RGR opsindependent pathway (44), and low-level rod function (Ͻ0.1%) persists in these mice via 9-cis-retinal (45,46). ipRGCs may have better access to these stores in rpe65 Ϫ/Ϫ or lrat Ϫ/Ϫ retinas with outer degeneration.…”

Section: Discussionmentioning

confidence: 99%

Inner retinal photoreception independent of the visual retinoid cycle

Tu¹,

Owens²,

Anderson³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Mice lacking the visual cycle enzymes RPE65 or lecithin-retinol acyl transferase (Lrat) have pupillary light responses (PLR) that are less sensitive than those of mice with outer retinal degeneration (rd͞rd or rdta). Inner retinal photoresponses are mediated by melanopsinexpressing, intrinsically photosensitive retinal ganglion cells (ipRGCs), suggesting that the melanopsin-dependent photocycle utilizes RPE65 and Lrat. To test this hypothesis, we generated rpe65 ؊/؊ ; rdta and lrat ؊/؊ ; rd͞rd mutant mice. Unexpectedly, both rpe65 ؊/؊ ; rdta and lrat ؊/؊ ; rd͞rd mice demonstrate paradoxically increased PLR photosensitivity compared with mice mutant in visual cycle enzymes alone. Acute pharmacologic inhibition of the visual cycle of melanopsin-deficient mice with all-trans-retinylamine results in a near-total loss of PLR sensitivity, whereas treatment of rd͞rd mice has no effect, demonstrating that the inner retina does not require the visual cycle. Treatment of rpe65 ؊/؊ ; rdta with 9-cis-retinal partially restores PLR sensitivity. Photic sensitivity in P8 rpe65 ؊/؊ and lrat ؊/؊ ipRGCs is intact as measured by ex vivo multielectrode array recording. These results demonstrate that the melanopsin-dependent ipRGC photocycle is independent of the visual retinoid cycle.melanopsin ͉ pupillary light response ͉ retinal degeneration ͉ retinal ganglion cell ͉ visual photocycle M ice blind from outer retinal degeneration retain the ability to entrain their circadian rhythms to external light-dark cycles, have active pupillary light responses (PLRs), and exhibit photically induced melatonin suppression (1-4). These responses depend on the opsin family member melanopsin (5), which is expressed exclusively in a subset of intrinsically photosensitive retinal ganglion cells (ipRGCs) (6-8). Mice with nonfunctional or degenerated rods and cones that also lack melanopsin show no photically influenced behavior or physiology (9, 10), and intrinsic photosensitivity of retinal ganglion cells is lost in the absence of melanopsin (9,11,12). Melanopsin forms a functional photopigment when heterologously expressed in COS cells (13), Xenopus oocytes (14), Neuro-2A cells (15), or HEK-293 cells (16). Melanopsin is thus necessary for ipRGC photoreception, and is sufficient to confer photosensitivity on intrinsically insensitive cell types. Taken together, these results strongly suggest that melanopsin is the photopigment of inner retinal photoreception.All opsin photopigments use a retinoid chromophore that undergoes isomerization upon absorption of an appropriate wavelength photon. In rod photoreceptors, 11-cis-retinal chromophore is photoisomerized to all-trans-retinal which dissociates from the opsin protein (17). This all-trans-retinal photoproduct is recycled to the active (11-cis) form by enzymatic conversion in the adjacent retinal pigment epithelium (RPE) (18). The chromophore used by melanopsin in situ is not presently known. ipRGCs are physically distant from the enzymatic chromophore regeneration machinery of the RPE. It is present...

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Section: Discussionmentioning

confidence: 99%

Inner retinal photoreception independent of the visual retinoid cycle

Tu¹,

Owens²,

Anderson³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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“…8). All-trans-retinal is utilized by retinal G-protein-coupled receptor, a hypothetical photoisomerase that is essential for replenishing 11-cis-retinals at high illumination levels (38). It has been proposed that RDH5 forms a complex with this retinal G-protein-coupled receptor (39).…”

Section: Dual-substrate Specificity Dual Responsibility; Mechanisticmentioning

confidence: 99%

Dual-substrate Specificity Short Chain Retinol Dehydrogenases from the Vertebrate Retina

Haeseleer¹,

Jang²,

Imanishi³

et al. 2002

Journal of Biological Chemistry

188

227

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Retinoids are chromophores involved in vision, transcriptional regulation, and cellular differentiation. Members of the short chain alcohol dehydrogenase/reductase superfamily catalyze the transformation of retinol to retinal. Here, we describe the identification and properties of three enzymes from a novel subfamily of four retinol dehydrogenases (RDH11-14) that display dualsubstrate specificity, uniquely metabolizing all-trans-and cis-retinols with C 15 pro-R specificity. RDH11-14 could be involved in the first step of all-trans-and 9-cis-retinoic acid production in many tissues. RDH11-14 fill the gap in our understanding of 11-cis-retinal and all-trans-retinal transformations in photoreceptor (RDH12) and retinal pigment epithelial cells (RDH11). The dualsubstrate specificity of RDH11 explains the minor phenotype associated with mutations in 11-cisretinol dehydrogenase (RDH5) causing fundus albipunctatus in humans and engineered mice lacking RDH5. Furthermore, photoreceptor RDH12 could be involved in the production of 11-cis-retinal from 11-cis-retinol during regeneration of the cone visual pigments. These newly identified enzymes add new elements to important retinoid metabolic pathways that have not been explained by previous genetic and biochemical studies.Retinoids are indispensable light-sensitive elements of vision and also serve as essential modulators of cellular differentiation and proliferation in diverse cell types, including those comprising the epithelium and immune system. Retinoids modulate the growth of both normal and malignant cells through their binding to retinoid receptors. All-trans-retinoic acid signals through specific interactions with the nuclear retinoic acid receptors, whereas its isomer, 9-cis-retinoic acid, is a high affinity ligand of retinoic acid receptors and retinoid X receptors. In the retina, light-dependent photoisomerization of 11-cis-retinylidene to the all-transretinylidene moiety of rod and cone photoreceptors is a key reaction that triggers visual * This research was supported by National Institutes of Health Grants EY08061, CA75173, and DK59125, a grant from Research to Prevent Blindness, Inc. (to the Department of Ophthalmology, University of Washington), and by the E. K. Bishop Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. S The on-line version of this article (available at http://www.jbc.org) contains Supplemental Figs. 1 and 2 and Tables 1-3. § These authors contributed equally to this work. § § Recipient of a Research to Prevent Blindness Senior Investigator Award. To whom correspondence should be addressed: Dept. of Ophthalmology, University of Washington, Seattle,; E-mail: palczews@u.washington.edu. Transformations of retinoids occur mostly through enzymatic or photochemical reactions, although they readily isomerize non-enzymatically to thermodynamic equilibriu...

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“…Another non-visual opsin is "retinal G proteincoupled receptor" (RGR) opsin, which is expressed in the internal membranes of RPE and Müller glial cells (9). RGR opsin may function as a photoisomerase that regenerates visual chromophore based on the phenotype of mice that lack RGR opsin (10) and its similarity to the known photoisomerase squid retinochrome (11). RGR opsin was also shown to affect light-dependent mobilization of all-trans-retinyl esters (all-trans-REs) in mouse RPE cells (12).…”

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confidence: 99%

Peropsin modulates transit of vitamin A from retina to retinal pigment epithelium

Ng¹,

Lloyd²,

Eddington³

et al. 2017

Journal of Biological Chemistry

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Edited by Velia M. FowlerPeropsin is a non-visual opsin in both vertebrate and invertebrate species. In mammals, peropsin is present in the apical microvilli of retinal pigment epithelial (RPE) cells. These structures interdigitate with the outer segments of rod and cone photoreceptor cells. RPE cells play critical roles in the maintenance of photoreceptors, including the recycling of visual chromophore for the opsin visual pigments. Here, we sought to identify the function of peropsin in the mouse eye. To this end, we generated mice with a null mutation in the peropsin gene (Rrh). These mice exhibited normal retinal histology, normal morphology of outer segments and RPE cells, and no evidence of photoreceptor degeneration. Biochemically, Rrh ؊/؊ mice had ϳ2-fold higher vitamin A (all-trans-retinol (all-trans-ROL)) in the neural retina following a photobleach and 5-fold lower retinyl esters in the RPE. This phenotype was similar to those reported in mice that lack interphotoreceptor retinoid-binding protein (IRBP) or cellular retinol-binding protein, suggesting that peropsin plays a role in the movement of all-trans-ROL from photoreceptors to the RPE. We compared the phenotypes in mice lacking both peropsin and IRBP with those of mice lacking peropsin or IRBP alone and found that the retinoid phenotype was similarly severe in each of these knock-out mice. We conclude that peropsin controls all-trans-ROL movement from the retina to the RPE or may regulate all-trans-ROL storage within the RPE. We propose that peropsin affects light-dependent regulation of all-trans-ROL uptake from photoreceptors into RPE cells through an as yet undefined mechanism.

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A photic visual cycle of rhodopsin regeneration is dependent on Rgr

Cited by 167 publications

References 21 publications

Inner retinal photoreception independent of the visual retinoid cycle

Inner retinal photoreception independent of the visual retinoid cycle

Dual-substrate Specificity Short Chain Retinol Dehydrogenases from the Vertebrate Retina

Peropsin modulates transit of vitamin A from retina to retinal pigment epithelium

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