Interaction of 11-cis-Retinol Dehydrogenase with the Chromophore of Retinal G Protein-coupled Receptor Opsin

Vertebrate opsins in both photoreceptors and the retinal pigment epithelium (RPE) have fundamental roles in the visual process. The visual pigments in photoreceptors are bound to 11-cis-retinal and are responsible for the initiation of visual excitation. Retinochrome-like opsins in the RPE are bound to all-trans-retinal and play an important role in chromophore metabolism. The retinal G protein-coupled receptor (RGR) of the RPE and Müller cells is an abundant opsin that generates 11-cis-retinal by stereospecific photoisomerization of its bound all-trans-retinal chromophore. We have analyzed a 32-kDa protein (p32) that co-purifies with bovine RGR from RPE microsomes. The co-purified p32 was identified by mass spectrometric analysis as 11-cis-retinol dehydrogenase (cRDH), and enzymatic assays have confirmed the isolation of an active cRDH. The co-purified cRDH showed marked substrate preference to 11-cis-retinal and preferred NADH rather than NADPH as the cofactor in reduction reactions. cRDH did not react with endogenous all-trans-retinal bound to RGR but reacted specifically with 11-cis-retinal that was generated by photoisomerization after irradiation of RGR. The reduction of 11-cis-retinal to 11-cis-retinol by cRDH enhanced the net photoisomerization of all-trans-retinal bound to RGR. These results indicate that cRDH is involved in the processing of 11-cis-retinal after irradiation of RGR opsin and suggest that cRDH has a novel role in the visual cycle. Vertebrate opsins in both photoreceptors and the retinal pigment epithelium (RPE) have fundamental roles in the visual process. The visual pigments in photoreceptors are bound to 11-cis-retinal and are responsible for the initiation of visual excitation. Retinochrome-like opsins in the RPE are bound to all-trans-retinal and play an important role in chromophore metabolism. The retinal G protein-coupled receptor (RGR) of the RPE and Müller cells is an abundant opsin that generates 11-cis-retinal by stereospecific photoisomerization of its bound all-trans-retinal chromophore. We have analyzed a 32-kDa protein (p32) that co-purifies with bovine RGR from RPE microsomes. The co-purified p32 was identified by mass spectrometric analysis as 11-cis-retinol dehydrogenase (cRDH), and enzymatic assays have confirmed the isolation of an active cRDH. The co-purified cRDH showed marked substrate preference to 11-cis-retinal and preferred NADH rather than NADPH as the cofactor in reduction reactions. cRDH did not react with endogenous all-trans-retinal bound to RGR but reacted specifically with 11-cis-retinal that was generated by photoisomerization after irradiation of RGR. The reduction of 11-cis-retinal to 11-cis-retinol by cRDH enhanced the net photoisomerization of all-trans-retinal bound to RGR. These results indicate that cRDH is involved in the processing of 11-cis-retinal after irradiation of RGR opsin and suggest that cRDH has a novel role in the visual cycle. retinal pigment epithelium RPE retinal G protein-coupled receptor 11-cis-retinol dehydrogenase all-trans-retinol dehydrogenase high performance liquid chromatography tandem mass spectrometry The continual synthesis of rhodopsin by recombination of its apoprotein with the chromophore, 11-cis-retinal, is an essential process that maintains visual excitation (1Wald G. Nature. 1968; 219: 800-807Crossref PubMed Scopus (575) Google Scholar, 2Stryer L. Harvey Lect. 1991–1992; 87: 129-143PubMed Google Scholar). It has long been known that formation of 11-cis-retinal for regeneration of rhodopsin is dependent on retinoid metabolic reactions in the retinal pigment epithelium (RPE),1 where the majority of enzymes of the visual cycle are located (reviewed in Ref. 3Saari J.C. Investig. Ophthalmol. Vis. Sci. 2000; 41: 337-348PubMed Google Scholar). In the current model of the visual cycle, all-trans-retinal from bleached rhodopsin is reduced to all-trans-retinol by an all-trans-retinol-specific dehydrogenase (tRDH) located in photoreceptor outer segments (4Wald G. Hubbard R. J. Gen. Physiol. 1949; 32: 367-389Crossref PubMed Scopus (54) Google Scholar, 5Saari J.C. Garwin G.G. Van Hooser J.P. Palczewski K. Vision Res. 1998; 38: 1325-1333Crossref PubMed Scopus (112) Google Scholar, 6Rattner A. Smallwood P.M. Nathans J. J. Biol. Chem. 2000; 275: 11034-11043Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar). The all-trans-retinol is then delivered to the RPE, where it is converted by the lecithin:retinol acyltransferase to all-trans-retinyl ester (7Saari J.C. Bredberg D.L. J. Biol. Chem. 1989; 264: 8636-8640Abstract Full Text PDF PubMed Google Scholar, 8Ruiz A. Winston A. Lim Y.H. Gilbert B.A. Rando R.R. Bok D. J. Biol. Chem. 1999; 274: 3834-3841Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar). A key step in the visual cycle is performed by an isomerohydrolase that catalyzes the formation of 11-cis-retinol from all-trans-retinyl ester (9Rando R.R. J. Bioenerg. Biomembr. 1991; 23: 133-146PubMed Google Scholar, 10Deigner P.S. Law W.C. Canada F.J. Rando R.R. Science. 1989; 244: 968-971Crossref PubMed Scopus (155) Google Scholar). Alternatively, the isomerization of all-trans-retinol to 11-cis-retinol is achieved via an intermediate with an anhydro-like carbocation structure (11McBee J.K. Kuksa V. Alvarez R. de Lera A.R. Prezhdo O. Haeseleer F. Sokal I. Palczewski K. Biochemistry. 2000; 39: 11370-11380Crossref PubMed Scopus (87) Google Scholar). An 11-cis-retinol-specific dehydrogenase (cRDH) is able to oxidize 11-cis-retinol to 11-cis-retinal (12Lion F. Rotmans J.P. Daemen F.J.M. Bonting S.L. Biochim. Biophys. Acta. 1975; 384: 283-292Crossref PubMed Scopus (84) Google Scholar, 13Zimmerman W.F. Exp. Eye Res. 1976; 23: 159-164Crossref PubMed Scopus (24) Google Scholar, 14Saari J.C. Bredberg D.L. Noy N. Biochemistry. 1994; 33: 3106-3112Crossref PubMed Scopus (80) Google Scholar), which is transferred to the outer segments of photoreceptors for recombination with opsin to form rhodopsin. Under light-adapted conditions, the rate of synthesis of 11-cis-retinal must be sufficient for regeneration of steady-state levels of visual pigments (15Alpern M. J. Physiol. ( Lond. ). 1971; 217: 447-471Crossref PubMed Scopus (114) Google Scholar, 16Alpern M. Masseidvaag F. Ohba N. Vision Res. 1971; 11: 539-549Crossref PubMed Scopus (53) Google Scholar). Besides isomerohydrolase, another type of isomerase in the RPE may include the retinochrome-like visual pigment homologues peropsin or the RPE retinal G protein-coupled receptor (RGR) opsin (17Sun H. Gilbert D.J. Copeland N.G. Jenkins N.A. Nathans J. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 9893-9898Crossref PubMed Scopus (123) Google Scholar, 18Jiang M. Pandey S. Fong H.K.W. Investig. Ophthalmol. Vis. Sci. 1993; 34: 3669-3678PubMed Google Scholar). In contrast to the visual pigments, RGR is bound in the dark to endogenous all-trans-retinal and is localized to intracellular membranes in RPE and Müller cells (19Pandey S. Blanks J.C. Spee C. Jiang M. Fong H.K.W. Exp. Eye Res. 1994; 58: 605-614Crossref PubMed Scopus (70) Google Scholar, 20Hao W. Fong H.K.W. J. Biol. Chem. 1999; 274: 6085-6090Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). Upon illumination, all-trans-retinal bound to RGR is photoisomerized stereospecifically to the 11-cis isomer (20Hao W. Fong H.K.W. J. Biol. Chem. 1999; 274: 6085-6090Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). These results provide evidence that RGR may function to generate 11-cis-retinal in vivo and participate in a light-dependent photic visual cycle. A proposed mechanism of RGR function is that 11-cis-retinal dissociates from irradiated RGR and directly enters the pathway for regeneration of rhodopsin under photic conditions. A central hypothesis of the photoisomerase model is that exchange of the chromophore bound to RGR occurs and involves distinct geometrical isomers. Retinal must uncouple and bind anew to RGR through a stereospecific cycle that is driven by light energy. The observation that microsomal RGR can be labeled with 3H-labeled all-trans-retinal (21Shen D. Jiang M. Hao W. Tao L. Salazar M. Fong H.K.W. Biochemistry. 1994; 33: 13117-13125Crossref PubMed Scopus (79) Google Scholar) and that ∼50‥ of RGR isolated from RPE is in the form of the apoprotein (22Hao W. Fong H.K.W. Biochemistry. 1996; 35: 6251-6256Crossref PubMed Scopus (72) Google Scholar) suggests that the binding of retinal is reversible and that the process of binding and dissociation of the chromophore occursin vivo. One of the factors that may control Schiff base hydrolysis and dissociation of 11-cis-retinal from RGR in vivois specific protein interactions. We have observed that when RGR is isolated in digitonin solution from bovine RPE microsomes by immunoaffinity chromatography, it co-purifies consistently with a 32–34-kDa protein (p32) (22Hao W. Fong H.K.W. Biochemistry. 1996; 35: 6251-6256Crossref PubMed Scopus (72) Google Scholar). It is possible that the co-purified protein forms a physical complex or associates functionally with RGR. Hence, the identification of the co-purified p32 protein may provide important insights into the mechanism of RGR function. In this paper, we report the analysis and characterization of co-purified p32, which has been identified as 11-cis-retinol dehydrogenase of the RPE. We demonstrate enzymatic activity of the co-purified cRDH and discuss its potential role in RGR function. Digitonin was obtained from Calbiochem-Novabiochem. Hydroxylamine and all-trans-retinal were purchased from Sigma. 11-cis-Retinal was provided by Dr. Rosalie Crouch (Medical University of South Carolina, Charleston, SC). An 11-cis-retinol standard was prepared by reduction of 11-cis-retinal in the presence of NaBH4 and was purified by high performance liquid chromatography (HPLC) as described previously (23Landers G.M. Methods Enzymol. 1990; 189: 70-80Crossref PubMed Scopus (21) Google Scholar). Organic solvents were HPLC grade. Dichloromethane and hexane were obtained from Fisher. Ether and methanol were from J. T. Baker Inc. Dioxane was from Burdick & Jackson. All isolation procedures were performed under dim red light. RPE cells were isolated from fresh bovine eyes, as described previously (22Hao W. Fong H.K.W. Biochemistry. 1996; 35: 6251-6256Crossref PubMed Scopus (72) Google Scholar). The cells were washed in ice-cold 0.25m sucrose, 30 mm sodium phosphate buffer, pH 6.5, and homogenized in a glass Dounce homogenizer. After a low speed centrifugation at 300 × g, the homogenate was centrifuged at 15,000 × g for 20 min at 4 °C. RPE microsomes in the supernatant were sedimented by centrifugation at 150,000 × g for 1 h at 4 °C and stored at −80 °C until later use. For isolation of RGR, the microsomal membranes were extracted three times for 1 h at 4 °C with 1.2‥ digitonin solution containing 10 mm sodium phosphate, pH 6.5, 150 mm NaCl, and 0.5 mm EDTA. The extracts were centrifuged each time at 100,000 × g for 20 min at 4 °C. The pooled supernatants were incubated overnight at 4 °C with Affi-Gel 10 resin (Bio-Rad) conjugated to monoclonal antibody 2F4, which is directed to the carboxyl terminus of bovine RGR (21Shen D. Jiang M. Hao W. Tao L. Salazar M. Fong H.K.W. Biochemistry. 1994; 33: 13117-13125Crossref PubMed Scopus (79) Google Scholar). The resin was transferred to a column and washed with 25 bed volumes of wash buffer (0.1‥ digitonin in 10 mm sodium phosphate, pH 6.5, 150 mm NaCl, and 0.5 mm EDTA). RGR was eluted from the column with 10 times 0.5 bed volumes of wash buffer containing 50 μm bovine RGR carboxyl-terminal peptide (CLSPQRREHSREQ). The eluted fractions were pooled and a The were analyzed by and with The of isolated protein was with a by of and with known of bovine protein The of RGR in was on a of isolated from In a of the isolation was in for the isolation of RGR from RPE as in RGR was in a and with A 32-kDa protein (p32) was to consistently with RGR. The p32 protein was from the and for a U. C. J. PubMed Scopus Google Scholar). A of the peptide was analyzed a liquid chromatography Chem. Scopus Google Scholar) directly to a mass as described previously J. 1998; PubMed Scopus Google Scholar). Full mass high and were the of the The protein identification was by the to the protein base the base J.K. J. 1994; PubMed Scopus Google Scholar). The reduction activity of cRDH was as described previously (12Lion F. Rotmans J.P. Daemen F.J.M. Bonting S.L. Biochim. Biophys. Acta. 1975; 384: 283-292Crossref PubMed Scopus (84) Google Scholar, S. M. Biochim. Biophys. Acta. 1993; PubMed Scopus Google Scholar). The was to the by retinal and S. J. Biol. Chem. Full Text PDF PubMed Google Scholar). The RGR or RPE microsomal were as the of cRDH For the reduction of the substrate solution 10 of retinal 1.2‥ 1 mm NADH or and sodium buffer, pH were performed by the NADH or NADPH cofactor or by of a protein The reactions were by the of 50 of substrate solution to 50 of protein After at the reactions were by of 0.5 of of and of were and the were incubated for 30 min at The were centrifuged at on a for 1 50 of was to each supernatant to was at was as a for the The of retinal isomer was by with a NADH and NADPH were prepared in mm pH The retinal chromophore of RGR was extracted under dim red light and analyzed by the of as described by Daemen F.J.M. PubMed Scopus Google Scholar, Daemen F.J.M. Biochim. Biophys. Acta. PubMed Scopus Google Scholar). In a of purified RGR were with of pH 6.5, and then 300 of methanol and 300 of The was to by the of 10 phosphate buffer, pH 6.5, containing 150 mm and 0.5 mm EDTA. The with by was performed by for 30 After centrifugation at for 1 the was and the was extracted with 300 of The were pooled and under a The extracted were then in of through glass and under The was stored in at −80 °C or analyzed by The of were analyzed by as described previously (20Hao W. Fong H.K.W. J. Biol. Chem. 1999; 274: 6085-6090Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). The extracted were in hexane and to a column × The HPLC was with a model and model The were and the were in a of hexane with and with rate of 1 The HPLC column was and of the was on the times of the known was at and the were analyzed with the The of each isomer in the was from the of both its and and was on the in 11-cis and Daemen F.J.M. Biochim. Biophys. Acta. PubMed Scopus Google Scholar, K. A. R. T. Vision Res. PubMed Scopus Google Scholar). was with and analyzed by as described In the were on a column × 150 a HPLC The were in a of hexane with and and 11-cis-retinol were with a at and was than that of The were analyzed with the of 11-cis-retinol was on the time of a purified The 11-cis-retinol standard was prepared from known 11-cis-retinal, as described previously (23Landers G.M. Methods Enzymol. 1990; 189: 70-80Crossref PubMed Scopus (21) Google Scholar). The HPLC was with of 11-cis-retinol and RGR was irradiated with light an light with a light at were by the light through a and long control were under dim red but were The RGR in 10 phosphate, pH 6.5, 150 mm NaCl, 0.5 and and were incubated in the presence of mm NADH cofactor or in buffer as under NADH was prepared in mm buffer, pH The was by the of 10 mm sodium phosphate, pH 6.5, 150 mm NaCl, and 0.5 mm EDTA. were performed for the time at °C in a from the light After of the of the was of the and was to the The retinal chromophore was extracted by and analyzed by as described The of RGR at °C rather than did not the of retinal from irradiated RGR. RPE microsomal were extracted in 1.2‥ digitonin solution at pH 6.5, and RGR was purified by immunoaffinity chromatography under dim red light. Under conditions, a 32-kDa protein (p32) was to with RGR The p32 protein was in by with It was not on by the antibody that was to the immunoaffinity when the were not The of p32 that was co-purified with RGR was by the of in the isolation 1 the antibody binding of the immunoaffinity column were by with RGR p32 was eluted from the column 1 and p32 did not as a The p32 was from a and analyzed by liquid chromatography the were to the base of known protein a of to 11-cis-retinol a known of the visual cycle spectrometric identification of The co-purified p32 was from the in 1 The protein was to and the peptide were analyzed by liquid chromatography The were to the base of known protein of p32 that the of 11-cis-retinol dehydrogenase are by the of the and mass for the are high to the and of the to the peptide of the peptide that was to the protein of the and J. 11: PubMed Scopus Google Scholar) are with observed An was performed to the presence of active cRDH in of RGR. 11-cis-retinal was as the The reduction of 11-cis-retinal was by its and was dependent on the of RGR to the The activity the NADH The reduction activity of cRDH was to each step in the of RGR and was RGR was not These that cRDH is co-purified with RGR in a solution and an active that cRDH from its the in photoreceptor are substrate and cofactor of the These of the dehydrogenase were in of RGR to the co-purified cRDH. The cRDH in RGR reacted with 11-cis-retinal but not with all-trans-retinal 4 cRDH preferred NADH rather than NADPH as the cofactor in the reduction A and For the activity of cRDH in RPE microsomal membranes was microsomal cRDH was active in the reduction of 11-cis-retinal, and was activity with all-trans-retinal as the substrate The in the microsomal membranes activity with NADH or These observed of microsomal cRDH were with the results of (12Lion F. Rotmans J.P. Daemen F.J.M. Bonting S.L. Biochim. Biophys. Acta. 1975; 384: 283-292Crossref PubMed Scopus (84) Google Scholar, 13Zimmerman W.F. Exp. Eye Res. 1976; 23: 159-164Crossref PubMed Scopus (24) Google Scholar, 14Saari J.C. Bredberg D.L. Noy N. Biochemistry. 1994; 33: 3106-3112Crossref PubMed Scopus (80) Google Scholar). cRDH specifically with 11-cis-retinal, the role of co-purified cRDH in RGR function may be to and bound 11-cis-retinal from RGR after stereospecific photoisomerization of its all-trans-retinal chromophore. In cRDH reduction activity was not observed the cofactor was not (20Hao W. Fong H.K.W. J. Biol. Chem. 1999; 274: 6085-6090Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). RGR was in the dark or irradiated with light. each was incubated in the dark in the presence or of The chromophore extracted from RGR was as and with NADH on the chromophore in the dark The irradiation of RGR and in the dark NADH in stereospecific isomerization of of the bound all-trans-retinal to 11-cis-retinal results were in with (20Hao W. Fong H.K.W. J. Biol. Chem. 1999; 274: 6085-6090Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). RGR was irradiated and then incubated in the dark in the presence of was a in The in retinal was by the of 11-cis-retinal with on the of the isomer in the chromophore of RGR were when NADH was irradiation of RGR. Under in which the cofactor is and cRDH is irradiation of RGR in of both and retinal that 11-cis-retinal was reduced by the co-purified cRDH with of the we the of 11-cis-retinol irradiation of RGR in the presence of The retinoid extracts from irradiated of RGR were analyzed after to light for of was at to the of The irradiation of RGR in the presence of NADH in of all-trans-retinal and a in 11-cis-retinol The of 11-cis-retinol to the of all-trans-retinal at the of 11-cis-retinol the in all-trans-retinal in the min of cRDH the 11-cis isomer we that the in 11-cis-retinol is to the of cRDH on or bound 11-cis-retinal, the photoisomerization of irradiated RGR. The RGR opsin is a protein in the RPE. evidence that the processing of all-trans-retinol and its into the chromophore of RGR in the dark has been obtained J. L. H. K. Scholar). of RGR results in stereospecific of the bound all-trans-retinal to be to the chromophore to or from RGR, the mechanism by which RGR may on specific protein interactions. In this paper, we demonstrate in the RGR opsin and cRDH. the isolation of purified RGR from bovine RPE results in of cRDH in a that suggests that cRDH to RGR in a protein In the presence of of cRDH was and of cRDH was as and specific as that of RGR in A of is to the protein complex and binding to the resin T. J. J. Methods Enzymol. 1991; PubMed Scopus Google Scholar). The co-purified was active and to of microsomal cRDH (12Lion F. Rotmans J.P. Daemen F.J.M. Bonting S.L. Biochim. Biophys. Acta. 1975; 384: 283-292Crossref PubMed Scopus (84) Google Scholar, 13Zimmerman W.F. Exp. Eye Res. 1976; 23: 159-164Crossref PubMed Scopus (24) Google Scholar, 14Saari J.C. Bredberg D.L. Noy N. Biochemistry. 1994; 33: 3106-3112Crossref PubMed Scopus (80) Google Scholar), isolated cRDH S. M. Biochim. Biophys. Acta. 1993; PubMed Scopus Google Scholar), or cRDH A. U. C. U. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, de Investig. Ophthalmol. Vis. Sci. Google Scholar). It was in the reduction of 11-cis-retinal and with the NADH was preferred NADPH as a cofactor in the reduction In microsomal cRDH activity was with both NADH and NADPH the presence in the RPE of cRDH activity that NADPH (12Lion F. Rotmans J.P. Daemen F.J.M. Bonting S.L. Biochim. Biophys. Acta. 1975; 384: 283-292Crossref PubMed Scopus (84) Google Scholar, J.K. Haeseleer F. Palczewski K. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar), of the with RGR was not was the substrate of cRDH in reactions with the chromophore of RGR. The co-purified was to all-trans-retinal bound to RGR in the dark but active endogenous 11-cis-retinal that was generated by irradiation of RGR. The cRDH was with RGR a of and its activity did not of the in the presence of as previously S. M. Biochim. Biophys. Acta. 1993; PubMed Scopus Google Scholar). The of RGR and cRDH may in the mechanism of chromophore dissociation from RGR. rhodopsin and visual pigments R. J. Gen. Physiol. 41: PubMed Scopus Google Scholar, S. Physiol. PubMed Scopus Google Scholar), the chromophore of RGR opsin not after photoisomerization in and irradiation not to of RGR, as by and after light (22Hao W. Fong H.K.W. Biochemistry. 1996; 35: 6251-6256Crossref PubMed Scopus (72) Google Scholar). RGR in vivo as a stereospecific photoisomerase to directly generate the 11-cis chromophore in the visual cycle, then all-trans-retinal be photoisomerized and 11-cis-retinal be from RGR The on irradiation of RGR were NADH and achieved at ∼50‥ net of to 11-cis-retinal (20Hao W. Fong H.K.W. J. Biol. Chem. 1999; 274: 6085-6090Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar). We can demonstrate photoisomerization of the bound all-trans-retinal to the 11-cis RGR is irradiated in the presence of isomerization of the chromophore is to reduction by cRDH. These results suggest that 11-cis-retinol is generated in a photic visual cycle. in processing of 11-cis-retinol include its to or binding to The results not an mechanism of dissociation and of 11-cis-retinal from RGR to protein or of protein on the RGR and cRDH. The of RGR with cRDH the evidence that RGR and rhodopsin have with The of RGR and rhodopsin are photoisomerized in each is bound to and all-trans-retinal at a specific of the After photoisomerization of the chromophore, 11-cis-retinal from RGR is reduced by and all-trans-retinal from rhodopsin is reduced by to the The cRDH and are A. Smallwood P.M. Nathans J. J. Biol. Chem. 2000; 275: 11034-11043Abstract Full Text Full Text PDF PubMed Scopus (171) Google Scholar, A. U. C. U. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, de Investig. Ophthalmol. Vis. Sci. Google Scholar). The reduction of all-trans-retinal in the of rhodopsin and is a step of the visual cycle at high light levels J.C. Garwin G.G. Van Hooser J.P. Palczewski K. Vision Res. 1998; 38: 1325-1333Crossref PubMed Scopus (112) Google Scholar). The is with the outer segments Biophys. Res. 94: PubMed Scopus Google Scholar, C. J. Biol. Chem. Full Text PDF PubMed Google Scholar, S. M. K. J. Biol. Chem. 1991; Full Text PDF PubMed Google Scholar, K. S. J. Crouch R. Bredberg D.L. J.C. Biochemistry. 1994; 33: PubMed Scopus Google its in the outer and possible binding to rhodopsin are In is evidence that the of cRDH in the RPE is the of the A. A. A. U. J. Sci. 1999; PubMed Google Scholar). of cRDH suggests that 11-cis-retinal from irradiated RGR is reduced by cRDH and at the of the for or processing of the The of the 11-cis-retinal reduction cRDH and RGR to be vivo role for cRDH was proposed by (12Lion F. Rotmans J.P. Daemen F.J.M. Bonting S.L. Biochim. Biophys. Acta. 1975; 384: 283-292Crossref PubMed Scopus (84) Google Scholar). of the visual cycle then have the of cRDH to rhodopsin with 11-cis-retinol in has Exp. Eye Res. PubMed Scopus Google Scholar, S. Science. PubMed Scopus Google Scholar, J. Gen. Physiol. PubMed Scopus Google Scholar). the pigments in can be with 11-cis-retinol Crouch Proc. Natl. Acad. Sci. U. S. A. 1989; PubMed Scopus Google Scholar). In this the reduction of 11-cis-retinal from RGR to 11-cis-retinol be sufficient for chromophore synthesis by the RPE in a visual cycle. Alternatively, the 11-cis-retinol from RGR may be converted to the ester for or as a intermediate in the synthesis of results provide a for a role of cRDH in to its role in of The of RGR and cRDH in a pathway may generate insights into the in of that in the cRDH H. S. U. 1999; PubMed Scopus Google Scholar, J. D. S. Scholar). We Hao and for and

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