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Highly Efficient Retinal Metabolism in Cones

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Highly Efficient Retinal Metabolism in Cones Highly efficient retinal metabolism in cones Sadaharu Miyazono*, Yoshie Shimauchi-Matsukawa*, Shuji Tachibanaki*†, and Satoru Kawamura*†‡ *Graduate School of Frontier Biosciences and †Department of Biology, Graduate School of Science, Osaka University, Suita, Osaka 565-0871, Japan Edited by Carter Cornwall, Boston University School of Medicine, Boston, MA, and accepted by the Editorial Board August 26, 2008 (received for review July 8, 2008) After bleaching of visual pigment in vertebrate photoreceptors, has been suggested: Mu¨ller cells can isomerize all-trans retinol to all-trans retinal is reduced to all-trans retinol by retinol dehydro- 11-cis retinol (11). When this 11-cis retinol is transported to genases (RDHs). We investigated this reaction in purified carp rods cones, it can be oxidized to 11-cis retinal with a hypothesized and cones, and we found that the reducing activity toward all- enzyme, 11-cis retinol dehydrogenase, that was assumed to be trans retinal in the outer segment (OS) of cones is >30 times higher present in cones and requires NADPϩ as a cofactor (12). than that of rods. The high activity of RDHs was attributed to high In the present study, by using purified carp (Cyprinus carpio) content of RDH8 in cones. In the inner segment (IS) in both rods and rods and cones (13), we investigated the metabolism of all-trans cones, RDH8L2 and RDH13 were found to be the major enzymes retinal and 11-cis retinal within the photoreceptor cells. We among RDH family proteins. We further found a previously unde- found that the reduction of all-trans retinal and the production scribed and effective pathway to convert 11-cis retinol to 11-cis of 11-cis retinal are both much more efficient in cones. In retinal in cones: this oxidative conversion did not require NADP؉ addition, it was found that 11-cis retinal is formed from 11-cis and instead was coupled with reduction of all-trans retinal to retinol by a previously undescribed retinal-retinol redox all-trans retinol. The activity was >50 times effective than the (ALOL)-coupling reaction. -oxidizing activity of RDHs that require NADP؉. These highly effec tive reactions of removal of all-trans retinal by RDH8 and produc- Results tion of 11-cis retinal by the coupling reaction are probably the Highly Efficient Reduction of all-trans Retinal in Cones. All-trans underlying mechanisms that ensure effective visual pigment re- retinal formed in the bleached visual pigment is reduced to generation in cones that function under much brighter light con- all-trans retinol. Fig. 1A shows the time courses of the reduction ditions than rods. of the exogenously applied all-trans retinal to all-trans retinol measured in the lysate of purified carp rods and cones. We 11-cis retinal ͉ 11-cis retinol ͉ all-trans retinal ͉ retinol dehydrogenase ͉ routinely quantified the amount of rods and cones by measuring visual cycle the amount of visual pigment in a sample. Therefore, the activity of the reduction of all-trans retinal, defined as the RDH activity ight detection in vertebrates is mediated by rods and cones. in this study, is expressed in units per visual pigment present. LBoth rods and cones consist of two parts, the outer segment This expression is useful in the comparison of the RDH activities (OS) and the inner segment (IS). The OS contains the machinery per unit volume of the OS between rods and cones, because the responsible for conversion of a light signal to an electrical signal. density of the visual pigment in the OS is similar between rods The light-absorbing molecule, the visual pigment, is present in and cones (14). However, most of our purified rods and cones the OS and is composed of a chromophore, 11-cis retinal, and a retained both the OS and the IS [see Materials and Methods and protein moiety, opsin. Light isomerizes 11-cis retinal to all-trans supporting information (SI) Fig. S1 A and E], and in addition, retinal, which induces a conformational change in opsin to lead both the OS and the IS showed the RDH activity (see below). to activation of an enzymatic cascade to evoke a light response For this reason, we show (Fig. 1) the activity in units per cell (rod (1, 2). or cone) by assuming that, on an average, a rod contains 1.6 ϫ All-trans retinal, the product formed after light absorption, 108, and a cone contains 7.8 ϫ 107 visual pigment molecules (13). then dissociates from opsin and is reduced to all-trans retinol. Later in the present study, we determine the RDH activity in the This form of retinol is transported to the retinal pigment OS, so that the activity will be expressed in units per visual epithelium (RPE), isomerized, and oxidized to 11-cis retinal with pigment present (after Fig. 2). multistep reactions. The newly synthesized 11-cis retinal is sent The RDH activity in rods was 1.6 Ϯ 0.2 amol of all-trans retinol back to photoreceptors to regenerate visual pigment. This formed per rod per second (amol atROL/rod-sec) (Fig. 1C). A pathway of retinal processing (visual cycle) has been mainly similar value of the RDH activity has been reported in bovine studied in rods or rod-dominant retinas (3, 4). Because cones rod OSs (ROSs) (15). The activity in cones was 12.4 Ϯ 1.4 amol function under much brighter light conditions, the visual cycle atROL/cone-sec (Fig. 1C). It was evident that the reducing for cones could differ from that for rods in a qualitative and/or activity per cell was approximately eight times higher in cones. quantitative way, as is seen in the phototransduction mechanism Our rod preparation contained small amounts of cones (13). in rods and cones (5, 6). Because cones showed much higher RDH activity than rods as The reduction of all-trans retinal to all-trans retinol is attained shown above, a correction for cone contamination in rod prep- by RDHs within a photoreceptor cell. This reduction could be arations was routinely made (see SI Materials and Methods). the rate-limiting step of the visual cycle (7), and the rate of the reduction has been reported to be 10–40 times higher in cones than in rods under in vivo conditions (8). The supply of 11-cis Author contributions: S.M., S.T., and S.K. designed research; S.M. and Y.S.-M. performed PHYSIOLOGY retinal to regenerate visual pigment could be faster in cones. research; S.M. analyzed data; and S.M., S.T., and S.K. wrote the paper. Several lines of evidence suggest that cone pigment is regener- The authors declare no conflict of interest. ated in an RPE-independent manner. For example, cone pig- This article is a PNAS Direct Submission. C.C. is a guest editor invited by the Editorial Board. ment, but not rod pigment, can be regenerated in isolated frog Data deposition: The sequences reported in this paper have been deposited in the GenBank retinas separated from the RPE (9). Interestingly, after bleach- database [accession nos. AB439579 (RDH8), AB439580 (RDH8L2), and AB439581 (RDH13)]. ing, photosensitivity recovers with addition of 11-cis retinol in ‡To whom correspondence should be addressed. E-mail: [email protected]. isolated cones but not in rods (10). These results suggest the This article contains supporting information online at www.pnas.org/cgi/content/full/ presence of a cone-specific regeneration pathway. Recently, an 0806593105/DCSupplemental. effective pathway for the supply of 11-cis retinal to opsin in cones © 2008 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0806593105 PNAS ͉ October 14, 2008 ͉ vol. 105 ͉ no. 41 ͉ 16051–16056 Downloaded by guest on September 25, 2021 Fig. 2. RDH activities in the OS and the IS of rods and cones. (A) Examples of SDS/PAGE patterns of ROS-rich, purified rod, and RIS-rich preparation, all Fig. 1. RDH activities in purified carp rods and cones. (A) Time course of containing constant 100 pmol of pigment (arrow). The RIS/ROS ratios in these reduction of all-trans retinal (RDH activity) in the rod and the cone lysate. The samples were 0.62, 1 and 2.9, respectively. (B) RDH activities as a function of activity is expressed as fmol of all-trans retinol formed per cell. The abscissa RIS/ROS ratio. (C) Estimated RDH activities in the ROS and in the RIS. The RDH indicates the time after addition of all-trans retinal. Error bars show standard activities in the ROS and in the RIS were calculated from the result shown in B deviations (n ϭ 4). (B) HPLC elution patterns of retinoids after 5-min incuba- (n ϭ 3). (D) Examples of SDS/PAGE patterns of COS-rich, purified cone, and tion of all-trans retinal (Left) with cone lysate (Upper Right) and rod lysate CIS-rich preparation, all containing constant 5 pmol of pigment (arrow). The (Lower Right). Arrowheads in Upper Right indicate (from left to right) 13-cis CIS/COS ratios in these samples were 0.14, 1 and 3.9, respectively. (E) RDH retinal, all-trans retinal, and all-trans retinol. Formation of 13-cis retinal is due activities as a function of CIS/COS ratio. (F) RDH activities in the COS and in the to nonspecific thermal isomerization from all-trans retinal (see Fig. 4B). (C) CIS were estimated from the result shown in E (n ϭ 4). RDH activities in the rod and the cone lysate. The activity was calculated from the results shown in A at 5 min (n ϭ 4).
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