New insights into retinoid metabolism and cycling within the retina

“Gene therapy studies on mouse (Pang et al., 2006) and canine (Acland et al., 2001, 2005) models, as well as LCA2 patients (Bainbridge et al., 2008; Maguire et al., 2008, 2009), have shown that inserting a functional gene for RPE65 into RPE cells holds great promise for restoring visual function.”

“, 2001, 2005) models, as well as LCA2 patients (Bainbridge et al., 2008; Maguire et al., 2008, 2009), have shown that inserting a functional gene for RPE65 into RPE cells holds great promise for restoring visual function.”

“Gene therapy studies on mouse (Pang et al., 2006) and canine (Acland et al., 2001, 2005) models, as well as LCA2 patients (Bainbridge et al., 2008; Maguire et al., 2008, 2009), have shown that inserting a functional gene for RPE65 into RPE cells holds great promise for restoring visual function.”

“Subsequently, bis-retinoids enter the RPE through the daily phagocytosis of photoreceptor outer segments (Young, 1967), ending up in the lysosomal compartmentwhere they accumulate in the form of lipofuscin.”

“All-trans retinal can form a Schiff base with amine groups, including the one on phosphatidylethanolamine, a major lipid component of OS membranes (Fliesler and Anderson, 1983).”

“Mice whose RPE65 gene has been knocked out (Rpe65 / ) do not generate 11-cis retinal (Redmond et al., 1998) and exhibit rapid cone loss and cone opsin”

“, 2007), a model for a pure-cone retina (Mears et al., 2001).”

“STRA6, the recently identified membrane receptor for plasma retinol binding protein (RPB), mediates the cellular uptake of trans retinol into the RPE (Kawaguchi et al., 2007; Sun, 2012).”

“In rod-dominant retinas such as in mice and humans, rods comprise over 94% of the total photoreceptor population (Carter-Dawson and LaVail,1979).”

“The rates of sensitivity recovery (Perry and McNaughton, 1991) and visual pigment regeneration (Schnapf et al., 1990) are greater in cones than in rods (Baylor et al., 1979, 1984).”

“Mutations to RPE65 are associated with Type 2 Leber congenital amaurosis (LCA2), an early onset congenital blindness that reduces or abolishes the innate synthesis of 11-cis retinal (Harris, 2001; Marlhens et al., 1997).”

“Phylogenetic analyses of opsin sequences demonstrate that opsins can be divided into 5 classes correlating roughly with absorption properties (Ebrey and Koutalos, 2001; Yokoyama, 2000).”

“…studies have shown that several species of rodents, notably thewell characterized and genetically-modified mouse, contain a mixture of the two cone opsins with a well-defined dorsal-ventral gradient across the retina, even in the wild-type animals (Applebury et al., 2000; Lukáts et al., 2005).”

“…concluded that RPE65 was the isomerohydrolase, most probably acting in complex with other retinyl-binding protein(s) and dehydrogenase(s), responsible for converting all-trans retinyl-ester to 11-cis retinol within the RPE (Jin et al., 2005; Moiseyev et al., 2005; Redmond et al., 2005).”

“The rates of sensitivity recovery (Perry and McNaughton, 1991) and visual pigment regeneration (Schnapf et al., 1990) are greater in cones than in rods (Baylor et al., 1979, 1984).”

“Gene therapy studies on mouse (Pang et al., 2006) and canine (Acland et al., 2001, 2005) models, as well as LCA2 patients (Bainbridge et al., 2008; Maguire et al., 2008, 2009), have shown that inserting a functional gene for RPE65 into RPE cells holds great promise for restoring visual function.”

“, 2010), but the best-studied bis-retinoid is still A2E (Eldred and Lasky, 1993; Parish et al., 1998; Sakai et al., 1995).”

“, 2010), but the best-studied bis-retinoid is still A2E (Eldred and Lasky, 1993; Parish et al., 1998; Sakai et al., 1995).”

“This information is directly comparable to fluorescence measurements; therefore, the spatial distributions of individual molecular ions (such as A2E, its oxides, precursors, and degradation products) can be determined and correlated with the measured fluorescence.”

“Müller cells contain CRBP and CRALBP, both of which are retinoid binding proteins found in the RPE, with the latter preferentially binding 11-cis retinoids (Bunt-Milam and Saari, 1983; Eisenfeld et al., 1985).”

“After b-carotene is absorbed by the intestinal lumen, it is symmetrically cleaved by b,b-carotene 15,150-monooxygenase into two molecules of all-trans retinal and eventually reduced to all-trans retinol by retinoid dehydrogenases (RDHs) (Redmond et al., 2001; von-Lintig and Vogt, 2000).”

“Phylogenetic analyses of opsin sequences demonstrate that opsins can be divided into 5 classes correlating roughly with absorption properties (Ebrey and Koutalos, 2001; Yokoyama, 2000).”

“Through interaction with blue light, lipofuscin was proposed to contribute to the development of age-related macular degeneration (Birnbach et al., 1994; Holz et al., 2001; Roberts et al., 2002).”

“…concluded that RPE65 was the isomerohydrolase, most probably acting in complex with other retinyl-binding protein(s) and dehydrogenase(s), responsible for converting all-trans retinyl-ester to 11-cis retinol within the RPE (Jin et al., 2005; Moiseyev et al., 2005; Redmond et al., 2005).”

“Diseases resulting in visual impairment arising from the disrupting retinoid metabolism have been recognized for some years and excellent reviews cover this area (Travis et al., 2007).”

“…concluded that RPE65 was the isomerohydrolase, most probably acting in complex with other retinyl-binding protein(s) and dehydrogenase(s), responsible for converting all-trans retinyl-ester to 11-cis retinol within the RPE (Jin et al., 2005; Moiseyev et al., 2005; Redmond et al., 2005).”

“Second, bis-retinoids constitute the major extractable component of lipofuscin (Kim et al., 2007; Sparrow et al., 2012).”

“Unlike the LRAT-dependent retinol esterification in the RPE, microsomes of chicken retina generated 11-cis retinyl-ester from all-trans retinol through a mechanism requiring palm-CoA as an acyl donor, suggesting this isomerase is dependent on acyl CoA-retinol acyltransferase (ARAT) (Muniz et al., 2009).”

“The cone-derived 661W cells (Tan et al., 2004) are known to have retinol esterase activity (Kanan et al.”

“The rates of sensitivity recovery (Perry and McNaughton, 1991) and visual pigment regeneration (Schnapf et al., 1990) are greater in cones than in rods (Baylor et al., 1979, 1984).”

“5; for reviews, see Muniz et al., 2007; Wang and Kefalov, 2011; Wolf, 2004).”

“RPE65 has been well-documented to be abundant in the RPE of many species (Hamel et al., 1993; Tsilou et al., 1997) and was originally proposed to be specific to that tissue.”

“The majority of the rod phototransduction proteins are associated with disc membranes isolated within the OS, whereas cone phototransductionproteins are embedded in theOSplasmamembrane that is arranged into stacked invaginations (Arikawa et al.,1992).”

“1 for retinoid structures) as its chromophore (Wald, 1935, 1951).”

“After b-carotene is absorbed by the intestinal lumen, it is symmetrically cleaved by b,b-carotene 15,150-monooxygenase into two molecules of all-trans retinal and eventually reduced to all-trans retinol by retinoid dehydrogenases (RDHs) (Redmond et al., 2001; von-Lintig and Vogt, 2000).”

“2; for review, see Mustafi et al., 2009) and make synaptic associations with secondary neurons such as bipolar cells in the outer plexiform layer (OPL).”

“Finally, all-trans retinal can form A2PE in rod OS membranes.”

“On the other hand, a detoxifying role for A2E itself has also been suggested as it removes the highly toxic free all-trans retinal (Maeda et al., 2011, 2009a; Roberts et al., 2002).”

“In vitrodata from several laboratories have shown that IRBP facilitates clearance of all-trans retinol from photoreceptor cells and uptake of 11-cis retinal from the RPE (Edwards and Adler, 2000; Jones et al., 1989).”

“Rod and cone opsins are members of the super-family of G-protein-coupled receptors (Shichida and Imai, 1998).”

“Recent in vitro studies of retinal release from cone opsins after bleaching compared to rhodopsin have shown that cone pigments release retinal at a much faster rate (M.H. Chen et al., 2012; Das et al., 2004; Hunt et al., 2009).”

“The rates of sensitivity recovery (Perry and McNaughton, 1991) and visual pigment regeneration (Schnapf et al., 1990) are greater in cones than in rods (Baylor et al., 1979, 1984).”

“In vitro studies had demonstrated up to nine oxygens could be detected on A2E exposed to oxidizing conditions (Ben-Shabat et al., 2002b); however, the tissue profiling studies only detected A2E with an addition of a maximum of 3 oxygens.”

“Through interaction with blue light, lipofuscin was proposed to contribute to the development of age-related macular degeneration (Birnbach et al., 1994; Holz et al., 2001; Roberts et al., 2002).”

“Gene therapy studies on mouse (Pang et al., 2006) and canine (Acland et al., 2001, 2005) models, as well as LCA2 patients (Bainbridge et al., 2008; Maguire et al., 2008, 2009), have shown that inserting a functional gene for RPE65 into RPE cells holds great promise for restoring visual function.”

“Retinal is a reactive aldehyde and a photosensitizer (Delmelle, 1978; Krasnovsky and Kagan, 1979; Matsumoto et al., 1975; Rozanowska and Sarna, 2005), and its toxicity may play a role in several diseases of the retina.”

“This was first shown for the guppy (Archer and Lythgoe, 1990) and the salamander (Makino and Dodd, 1996).”

“Consistent with this notion, mice that lack retinol dehydrogenases, the enzymes that oxidize all-trans retinol to retinal show increased A2E accumulation in the RPE (Chrispell et al., 2009; Maeda et al., 2005).”

“A crystal structure for RPE65 has been determined at 2.14 A resolution (Kiser et al., 2009).”

“…affect recovery of sensitivity by the rods as might have been expected if IRBP were critical for the transport of 11-cis retinal to photoreceptors (Palczewski et al., 1999; Ripps et al., 2000); however, Irbp / mice do exhibit rod degeneration (Liou et al., 1998), indicating that IRBP’s absence is…”

“This finding is particularly interesting considering the topology of Müller cell processes, as they make numerous associations with cones at this region (Sarantis and Mobbs, 1992; Wang et al., 2009).”

“Mice whose RPE65 gene has been knocked out (Rpe65 / ) do not generate 11-cis retinal (Redmond et al., 1998) and exhibit rapid cone loss and cone opsin mistrafficking (Fan et al., 2008; Tang et al., 2010; Znoiko et al., 2005).”

“Second, bis-retinoids constitute the major extractable component of lipofuscin (Kim et al., 2007; Sparrow et al., 2012).”

“Cultured chicken Müller cells were shown to convert all-trans retinol to alltrans and 11-cis palmitates and 11-cis retinol, similar to reactions in the classical visual cycle of the RPE (Das et al., 1992).”

“On the other hand, a detoxifying role for A2E itself has also been suggested as it removes the highly toxic free all-trans retinal (Maeda et al., 2011, 2009a; Roberts et al., 2002).”

“A2E formation from 11-cis retinal While it is clear that retinoids are involved in lipofuscin, recent evidence shows 11-cis retinal itself may be a major source of lipofuscin andA2E (Boyer et al., 2012).”

“From studies where the human rod RH1 pigment has been expressed in Xenopus M/L cones, and the human or salamander M/L cone pigment has been expressed in Xenopus rods, it has been clearly demonstrated that the respective cells have the same amplification and kinetics with either the rod or the cone opsin, thus eliminat…”

“Furthermore, successful use of small molecules and retinoid derivatives to ameliorate the cone degeneration reported in animal models of LCA2 has been reported (Maeda et al., 2009b; Rohrer et al., 2005).”

“…removal of all-trans retinal that occurs as a part of the light detection process is thought to be associated with the formation of lipofuscin (Katz and Redmond, 2001; Katz and Robinson, 2002; Sparrow et al., 2010), the fluorescent pigment that accumulates with age in the RPE lysosomal compartment.”

“Its involvement in promoting the cone visual cycle is supported byevidence that IRBP binds 11-cis retinol endogenously (Saari et al., 1985), is co-localized with Müller cell processes surrounding the cone cell body (Uehara et al.”

“…of sensitivity by the rods as might have been expected if IRBP were critical for the transport of 11-cis retinal to photoreceptors (Palczewski et al., 1999; Ripps et al., 2000); however, Irbp / mice do exhibit rod degeneration (Liou et al., 1998), indicating that IRBP’s absence is not benign.”

“This retinyl-ester is the substrate for the proposed isomerohydrolase, RPE65 (Moiseyev et al., 2003).”

“There has been recent interest in the use of retinoids and small molecules mimicking retinoids as therapeutic agents acting as inhibitors of the visual cycle as a means of preventing the accumulation of the lipofuscin that occurs in Stargardt’s disease and macular degeneration (Golczak et al., 2008; Maiti et al., 2006…”

“The loss of chromophore was also shown to take place in cones as well as in expressed and purified cone pigments; however, this did not occur with rods and rhodopsin (Kefalov et al., 2005).”

“Compounds representing a fraction of the structure of retinal have been known for some years to fit into the binding site of rhodopsin and to inhibit the binding of the native chromophore (Matsumoto and Yoshizawa, 1975; Nelson et al., 1970).”

“The isoform of RPE65 appears to affect the phenotype of Irbp / mice as Jin et al. (2009) reported cones in Irbp / mice with the Leu450 variant of RPE65 also had reduced outer segment length, partially mislocalized cone opsin, and underwent progressive degeneration.”

“The salamander green rod has been shown to have the same SWS2 opsin as the blue cone of that species (Ma et al., 2001).”

“There has been recent interest in the use of retinoids and small molecules mimicking retinoids as therapeutic agents acting as inhibitors of the visual cycle as a means of preventing the accumulation of the lipofuscin that occurs in Stargardt’s disease and macular degeneration (Golczak et al., 2008; Maiti et al., 2006…”

“As IRBP protects the isomeric state of 11-cis retinol, even in the presence of light (Crouch et al., 1992), the protein is likely to have a critical role in the delivery of 11-cis retinol to cones and to facilitate cone function.”

“Data to support this come from Lrat / mouse studies (Fan et al., 2008; Zhang et al., 2008), where the lack of esterification of alltrans retinol in the RPE, the substrate for RPE65-dependent isomerization (Moiseyev et al.”

“The first observations weremade using salamander rods and cones with measurements on isolated photoreceptors (Isayama et al., 2006; Jin et al., 1993; Kefalov et al., 1999).”

“Previous work in the isolated frog retina has also implicated the regeneration of 11-cis retinal by the retina independent of the RPE (Goldstein,1968; Hood and Hock, 1973).”

“Data to support this come from Lrat / mouse studies (Fan et al., 2008; Zhang et al., 2008), where the lack of esterification of alltrans retinol in the RPE, the substrate for RPE65-dependent isomerization (Moiseyev et al.”

“Imaging the fluorescence of retinol has permitted the study of its formation kinetics in isolated photoreceptors from several vertebrate species, including salamander (Ala-Laurila et al., 2006; Tsina et al., 2004), frog (Chen et al.”

“Knocking out IRBP in mice (Irbp / ) did not affect recovery of sensitivity by the rods as might have been expected if IRBP were critical for the transport of 11-cis retinal to photoreceptors (Palczewski et al., 1999; Ripps et al., 2000); however, Irbp / mice do exhibit rod degeneration (Liou et al.”

“The mechanism of action is still unclear, but recent studies support a carbocation mechanism (Redmond et al., 2010) as previously proposed (McBee et al., 2000).”

“There has been recent interest in the use of retinoids and small molecules mimicking retinoids as therapeutic agents acting as inhibitors of the visual cycle as a means of preventing the accumulation of the lipofuscin that occurs in Stargardt’s disease and macular degeneration (Golczak et al., 2008; Maiti et al., 2006…”

“IRBP is the most abundant soluble protein in the sub-retinal space (Gonzalez-Fernandez, 2003) and is known to bind retinoids (Edwards andAdler,1994; Pepperberg et al.,1993).”

“This was first shown for the guppy (Archer and Lythgoe, 1990) and the salamander (Makino and Dodd, 1996).”

“However, themRNA of RPE65 has been reported in the iris (Kociok et al., 1998), and the protein has been found in transformed kidney cells (Ma et al.”

“, 1985), is co-localized with Müller cell processes surrounding the cone cell body (Uehara et al., 1990), and is found in high concentrations around the cones (Carter-Dawson and Burroughs, 1992a, 1992b).”

“Third, lipofuscin accumulation requires the phagocytosis of the photoreceptor OS by the RPE, and in the absence of phagocytosis, retinoid-derived fluorescent material accumulates in the photoreceptors (Katz et al., 1987).”

“The images are oriented: dorsal e top; ventral e bottom; nasal laboratory utilized 8 mm tissue punches on human RPE and surprisingly found no correlation with the lipofuscin distribution reported by others (Bhosale et al., 2009; Wing et al., 1978).”

“Recent in vitro studies of retinal release from cone opsins after bleaching compared to rhodopsin have shown that cone pigments release retinal at a much faster rate (M.H. Chen et al., 2012; Das et al., 2004; Hunt et al., 2009).”

“On the other hand, a detoxifying role for A2E itself has also been suggested as it removes the highly toxic free all-trans retinal (Maeda et al., 2011, 2009a; Roberts et al., 2002).”

“The reduction requires NADPH (Futterman et al., 1970) and, at the same time, achieves both the removal of retinal and the initiation of the recycling of all-trans retinal back to the 11-cis form.”

“Retinylesters are composed of all-trans retinol bound to a fatty acid through an ester linkage that must be hydrolyzed for absorption to occur (Rigtrup and Ong,1992).”

“…studies have shown that several species of rodents, notably thewell characterized and genetically-modified mouse, contain a mixture of the two cone opsins with a well-defined dorsal-ventral gradient across the retina, even in the wild-type animals (Applebury et al., 2000; Lukáts et al., 2005).”

“1 for retinoid structures) as its chromophore (Wald, 1935, 1951).”

“There are numerous studies suggesting a toxic role for A2E to the RPE, particularly in its oxidized form (Kim et al., 2008; Wang et al., 2006).”

“Retinal is a reactive aldehyde and a photosensitizer (Delmelle, 1978; Krasnovsky and Kagan, 1979; Matsumoto et al., 1975; Rozanowska and Sarna, 2005), and its toxicity may play a role in several diseases of the retina.”

“Knocking down the expression of CRALBP in the Müller cells of zebrafish larvae by using antisense morpholinos results in a substantial decrease in 11-cis retinal and reduction in light sensitivity, supporting the key role of this protein (Collery et al., 2008; Fleisch et al., 2008).”

“Night blindness resulting from vitamin A deficiency was identified as the result of the rod photoreceptors lacking chromophore (Dowling, 1964), and indeed many of these studies led to the initial findings in retinoid cycling.”

“Retinal is a reactive aldehyde and a photosensitizer (Delmelle, 1978; Krasnovsky and Kagan, 1979; Matsumoto et al., 1975; Rozanowska and Sarna, 2005), and its toxicity may play a role in several diseases of the retina.”

“Using a polyclonal anti-RPE65 antibody generated from a synthetic peptide corresponding to residues 150e164 of bovine RPE65 (NFITKVNPETLETIK) (Redmond and Hamel, 2000), we showed localization of RPE65 in the OS of cones of thewild-type mice (Fig.”

“Themost common ester found in the retina is retinyl-palmitate (Trehan et al., 1990).”

“Further support for the existence of RPE65 in mouse cones comes from the Nrl / mouse, which contains elevated levels of RPE65 within the retinawhen compared to the wild-type mouse (Wenzel et al., 2007).”

“Surprisingly, the RPE65-based complex is not specific for the 11-cis isomer, but may be driven by a mass action effect of the binding protein(s) (Redmond et al., 2010).”

“, 2004), frog (Chen et al., 2005; Wu et al., 2007), gecko (Kolesnikov et al.”

“, 2004), frog (Chen et al., 2005; Wu et al., 2007), gecko (Kolesnikov et al.”

“5; for reviews, see Muniz et al., 2007; Wang and Kefalov, 2011; Wolf, 2004).”

“Interestingly, 11-cis retinol is now known to act as an agonist to rod opsin, activating the rod opsins in a light-independent manner (Kono et al., 2008).”

“Consistent with this notion, mice that lack retinol dehydrogenases, the enzymes that oxidize all-trans retinol to retinal show increased A2E accumulation in the RPE (Chrispell et al., 2009; Maeda et al., 2005).”

“Knocking down the expression of CRALBP in the Müller cells of zebrafish larvae by using antisense morpholinos results in a substantial decrease in 11-cis retinal and reduction in light sensitivity, supporting the key role of this protein (Collery et al., 2008; Fleisch et al., 2008).”

“This is in agreement with the faster release of retinal from the photoactivated visual pigment, and the higher retinol dehydrogenase activity in cones (Miyazono et al., 2008).”

“Hydroxylamine, which can disrupt the Schiff base linkage of 11-cis retinal by forming an oxime, has greater accessibility to the chromophore in the dark in most cone pigments than in rhodopsin (Fukada et al., 1990; Wald et al., 1955).”

“Müller cells contain CRBP and CRALBP, both of which are retinoid binding proteins found in the RPE, with the latter preferentially binding 11-cis retinoids (Bunt-Milam and Saari, 1983; Eisenfeld et al., 1985).”

“Several studies have shown that removal of the palmitate groups on rhodopsin has little effect on the functional properties except, surprisingly, that excessive light greatly accelerates retinal degeneration compared to wild-type animals (Maeda et al., 2010; Wang et al., 2005).”

“We have recently developed a method for the localization of bis-retinoid utilizing a mass spectrometry-based technique, MALDI imaging (Grey et al., 2011).”

“(AeB) Cross-section of lizard retina stained with Hematoxylin/Eosin (H&E) or Periodic Acid Schiff (PAS) shows cones with large IS and tapered OS, as previously described (Makaretz and Levine, 1980).”

“Retinal is a reactive aldehyde and a photosensitizer (Delmelle, 1978; Krasnovsky and Kagan, 1979; Matsumoto et al., 1975; Rozanowska and Sarna, 2005), and its toxicity may play a role in several diseases of the retina.”

“Further demonstration of oxidase activity in cones was shown in eyecups of mice that lacked endogenous 11-cis retinal from which 11-cis retinal could be generated after incubation with 11-cis retinol (Parker et al., 2011).”

“There are numerous studies suggesting a toxic role for A2E to the RPE, particularly in its oxidized form (Kim et al., 2008; Wang et al., 2006).”

“Cones in Irbp / mice were found to be retinoid-deficient under photopic conditions in two studies (Parker et al., 2009), leading to the proposal that 11-cis retinol supplies are disrupted in the absence of IRBP.”

“Recent in vitro studies of retinal release from cone opsins after bleaching compared to rhodopsin have shown that cone pigments release retinal at a much faster rate (M.H. Chen et al., 2012; Das et al., 2004; Hunt et al., 2009).”

“STRA6, the recently identified membrane receptor for plasma retinol binding protein (RPB), mediates the cellular uptake of trans retinol into the RPE (Kawaguchi et al., 2007; Sun, 2012).”

“Imaging the fluorescence of retinol has permitted the study of its formation kinetics in isolated photoreceptors from several vertebrate species, including salamander (Ala-Laurila et al., 2006; Tsina et al., 2004), frog (Chen et al.”

“Using suction electrodes to mask the OS of isolated salamander rods and cones, 11-cis retinal presented to the cell bodies of bleached photoreceptors restored light sensitivity in cones, but had no effect on rods (Jin et al., 1994).”

“RPE65 has been well-documented to be abundant in the RPE of many species (Hamel et al., 1993; Tsilou et al., 1997) and was originally proposed to be specific to that tissue.”

“In humans, RPE65 appears to be selectively expressed in the OS regions of cones that detect green/red light, but not in blue cones (Tang et al., 2011a).”

“RT-PCR analysis of isolated salamander photoreceptors first demonstrated the presence of RPE65 mRNA in cones, but not rods (Ma et al., 1998).”

“Several studies have shown that removal of the palmitate groups on rhodopsin has little effect on the functional properties except, surprisingly, that excessive light greatly accelerates retinal degeneration compared to wild-type animals (Maeda et al., 2010; Wang et al., 2005).”

“The first observations weremade using salamander rods and cones with measurements on isolated photoreceptors (Isayama et al., 2006; Jin et al., 1993; Kefalov et al., 1999).”

“11-cis Retinal serves as an inverse agonist to the opsins (Ala-Laurila et al., 2009) resulting in a reduction of the photoreceptor resting current.”

“ND ¼ not determined. a Data from Das et al. (2004). b Unpublished data from Kono and Crouch although a spectrum of 11-cis 13-demethyl retinal in bovine RH1 (Nelson et al., 1970) and an action spectrum of salamander rods regenerated with the same analog have been shown to have the same absorption…”

“Rhodopsin falls into the RH1 class of opsins; the human blue cone opsin is one form of a short wavelength-sensitive (SWS1) opsin that includes pigments that absorb maximally from about 350 to 440 nm; and the human red and green cone opsins are both medium/long wavelength-sensitive (M/LWS) opsins, which account for the…”

“In vitrodata from several laboratories have shown that IRBP facilitates clearance of all-trans retinol from photoreceptor cells and uptake of 11-cis retinal from the RPE (Edwards and Adler, 2000; Jones et al., 1989).”

“This finding is particularly interesting considering the topology of Müller cell processes, as they make numerous associations with cones at this region (Sarantis and Mobbs, 1992; Wang et al., 2009).”

“5; for reviews, see Muniz et al., 2007; Wang and Kefalov, 2011; Wolf, 2004).”

“Retinas obtained from (A) C57BL/6 or ght field; middle ¼ fluorescence images before bleaching; and the right panel ¼ after ars ¼ 5 mm. Data re-plotted from Chen et al. (2009). precursors of lipofuscin, such as A2PE, form in the photoreceptor OS from all-trans retinal that is escaping reduction to…”

“…the LRAT-dependent retinol esterification in the RPE, microsomes of chicken retina generated 11-cis retinyl-ester from all-trans retinol through a mechanism requiring palm-CoA as an acyl donor, suggesting this isomerase is dependent on acyl CoA-retinol acyltransferase (ARAT) (Muniz et al., 2009).”

“, 2010), but the best-studied bis-retinoid is still A2E (Eldred and Lasky, 1993; Parish et al., 1998; Sakai et al., 1995).”

“Methods of sustained delivery of the retinoids have also been developed for the potential use of these hydrophobic agents (Tang et al., 2010).”

“, 2007), gecko (Kolesnikov et al., 2007), and mouse (Blakeley et al.”

“, 1998), and the protein has been found in transformed kidney cells (Ma et al., 1999), human epidermis (Hinterhuber et al.”

“, 2004) are known to have retinol esterase activity (Kanan et al., 2008), and we found that 11-cis retinol can be esterified in these cells (Tang et al.”

“, 1999), human epidermis (Hinterhuber et al., 2004), and non-melanocytic skin tumors (Hinterhuber et al.”

“Mutations to RPE65 are associated with Type 2 Leber congenital amaurosis (LCA2), an early onset congenital blindness that reduces or abolishes the innate synthesis of 11-cis retinal (Harris, 2001; Marlhens et al., 1997).”

“In humans, RPE65 appears to be selectively expressed in the OS regions of cones that detect green/red light, but not in blue cones (Tang et al., 2011a).”

“…the study of its formation kinetics in isolated photoreceptors from several vertebrate species, including salamander (Ala-Laurila et al., 2006; Tsina et al., 2004), frog (Chen et al., 2005; Wu et al., 2007), gecko (Kolesnikov et al., 2007), and mouse (Blakeley et al., 2011; Chen et al., 2009).”

“…from Das et al. (2004). b Unpublished data from Kono and Crouch although a spectrum of 11-cis 13-demethyl retinal in bovine RH1 (Nelson et al., 1970) and an action spectrum of salamander rods regenerated with the same analog have been shown to have the same absorption maximum (Corson et al., 2000).”

“Consistent with these results, studies have demonstrated that a prolonged light-activated salamander red cone occurs in isolated salamander red cone cells regenerated with 11-cis 9-demethyl retinal (Estevez et al., 2006, 2009).”

“This 61 kDa protein undergoes post-translational modification with palmitates to facilitate association with membranes (Takahashi et al., 2006) and is homologous to beta-carotene oxygenases (Redmond et al.”

“Furthermore, chromophore has been demonstrated to be exchanged in the dark with cone pigments, but not rhodopsin (Crescitelli, 1984; Matsumoto et al., 1975).”

“The first observations weremade using salamander rods and cones with measurements on isolated photoreceptors (Isayama et al., 2006; Jin et al., 1993; Kefalov et al., 1999).”

“The shuttling of all-trans retinol from the photoreceptors to the RPE and 11-cis retinal from the RPE to the photoreceptors is presumably aided by a retinoid binding protein, interphotoreceptor retinoid binding protein (IRBP) (see Section 3.3) (Edwards and Adler, 1994, 2000).”

“Our recent findings that RPE65, the proposed isomerase in the RPE, is present within cones (Tang et al., 2011a, 2011b), and the unexpected distribution of the retinoid metabolite N-retinylidene-N-retinylethanolamine (A2E) (Ablonczy et al., 2012a, and see Fig.”

“SWS2 cone opsins have a single corresponding cysteine, and partial palmitoylation of salamander SWS2 cone opsin has been shown (Ablonczy et al., 2006).”

“A2E formation from 11-cis retinal While it is clear that retinoids are involved in lipofuscin, recent evidence shows 11-cis retinal itself may be a major source of lipofuscin andA2E (Boyer et al., 2012).”

“This structure is known to be composed of smooth ER and glycogen (Amemiya, 1975; Braekevelt, 1990); of a human retina immunostained for RPE65 shows the protein is localized within the uorescence, (B) composite of RPE65 and propidium iodide fluorescence, and (C) RPE65 . however the implications for…”

“, 2004), and non-melanocytic skin tumors (Hinterhuber et al., 2005).”

“Consistent with these results, studies have demonstrated that a prolonged light-activated salamander red cone occurs in isolated salamander red cone cells regenerated with 11-cis 9-demethyl retinal (Estevez et al., 2006, 2009).”

“Unexpectedly, it was found that such small molecules could also act as agonists or inverse agonists to opsins (Kono and Crouch, 2010, 2011).”

“a ligand-dependent manner as previously described (Kono and Crouch, 2011).”

“The small molecules have the advantage in not being light sensitive and also in not forming photoreactive pigments with the opsins (Fan et al., 2011).”

“8); this cycle regenerates 11-cis-retinal at a 20-fold faster rate (Mata et al., 2002; Tang et al., 2013), although all of the proteins in this cycle have not yet been identified.”

“The visual cycle is a series of biochemical reactions within the RPE and retina that is fundamental to vision (Tang et al., 2013; Travis et al., 2007).”

“In addition, vitamin A re-enters the visual cycle for re-isomerization and transport back to the photoreceptors for regeneration of the opsin visual pigments.(54) Our data confirm that in our model we successfully deleted Rb1cc1 from the RPE, and in this manner we were able to selectively prevent induction of canonica…”

“This may be explained for instance by the fact that cone photoreceptors can function relatively well despite the physical separation from the RPE because of mechanisms such as an alternative, intraretinal visual pigment regeneration route (Wang and Kefalov, 2011; Tang et al., 2013).”

“In order to provide a constant supply of 11-cis retinal, all-trans retinal must be converted back to 11-cis retinal through a series of redox reactions collectively referred to as the visual cycle [74].”

“Within these layers, the distinct cell types of the retina have well-defined physiological functions, the loss of which can result in eye diseases that cause loss of vision, such as age-related macular degeneration (AMD) [3], diabetic retinopathy [4, 5], Stargardt disease [6–8], and retinitis pigmentosa [9].”

“These include the expression of RPE-specific molecules such as BEST1, MERTK, RPE65, and CRALBP along with the capability to carry out phagocytosis, form adherence junctions, and produce cytokines (10, 11).”

“Sodium iodate (NaIO3) induces retinal degeneration with features similar to AMD [56].”

“Transducing light is the basis of all subsequent visual processing (Wald, 1945; Tang et al., 2013).”

“The transport of retinoids, mechanisms by which this chromophore is supplied to both rods and cones, and the metabolism of retinoids within the posterior segment of the eye, are reviewed in detail elsewhere [53].”

“On the one hand, the eye depends on visible light energy to ensure subsequent visual processing, but on the other, it can be damaged by the very same light in the form of acute high-dose or chronic UVR (Wald, 1945; Tang et al., 2013).”

“Recently, further evidence has also implicated IRBP in the retinoid exchange between cones and Müller cells (Tang et al., 2013).”

“Over the last 2 decades, progress towards understanding the chemistry and biology of vision at the molecular level has been substantial (11–15).”

“In fact, the fovea has the highest concentration of cones in the whole retina(6) and it is also exposed at the highest metabolic activity.(7,8) As a consequence, it is likely that a damaging process involving the photoreceptors either due to a direct targeting(4) or secondary to a transient decrease in the choriocapil…”

“Although its composition is not fully understood in any tissues, the lipofuscin in the RPE is known to be enriched in pyridinium bisretinoids [15, 16], which have a broad fluorescence emission spectrum similar to RPE lipofuscin [26].”

“Light is converted into electrical signals in the ROS, whereas the regeneration of 11-cis-Ral, an inherent chromophore of visual pigment, is accomplished in the RPE.(26) Since chromophore supplementation from choroid blood vessels in”

“Combining recycled 11-cis-retinal with opsins to form visual pigments completes chromophore regeneration and permits phototransduction and visual perception to continue [14-18].”

“It has been suggested that this protein might be involved in the cone visual cycle by acting as a retinol-binding protein (Tang et al., 2013 ).”

“…retinal undergoes photoisomerization to all-trans retinal which changes the conformation of the Opsin GPCR leading to signal transduction cascades causing closure of cyclic GMP-gated cation channel, and hyperpolarization of the photoreceptor cell (Shichida and Matsuyama, 2009; Tang et al., 2013).”

“An in-depth mechanistic understanding of the retinoid cycle in combination with relevant animal models promises to result in the establishment of successful interventions for human retinal disorders [1,5–8].”

“via either the canonical retinal pigment epithelium (RPE)-driven visual cycle (which delivers chromophore to both rods and cones) or the Müller cell–mediated retina visual cycle serving the cones exclusively (reviewed by Wang and Kefalov, 2011; Tang et al., 2013; Kiser et al., 2014).”

“Continuous function of photoreceptors requires release of the spent chromophore all-trans-retinal and its recycling back to 11-cis-retinal via either the retinal pigmented epithelium (RPE visual cycle, for both rods and cones) or Müller cells (retina visual cycle, for cones only) (reviewed by Wang & Kefalov, 2011; Tan…”

“The disease is thought to originate from a malfunctioning retinal pigment epithelium (RPE) a monolayer of cells that performs multiple roles required for survival and proper functionality of the photoreceptors, including fluid level regulation, visual pigment recycling, nutrient replenishment, and phagocytosis of phot…”

“An essential step of the visual cycle, isomerization of all-trans- retinyl ester to 11-cis-retinol is catalysed by retinal pigment epithelium-specific 65 kDa protein (RPE65) [8,9].”

“This phototransduction involves the isomerization of retinoids and the subsequent activation of other signaling molecules in an amplifying cascade (Tang et al. 2013).”

“The latter will be reduced to all-trans-retinol (atROL) in the photoreceptor cytoplasm by retinol dehydrogenase 8 (RDH8), RDH11, and RDH12 (3, 4). atROL, also called vitamin A, can be isomerized into 11-cis-retinol (11-cis-ROL) in the RPE via RPE65, the visual cycle retinol isomerase (5).”

“The released all-trans retinal is reduced within the rod outer segment to all-trans retinol, which is then transported to the RPE where it is recycled to make 11-cis retinal (Lamb and Pugh, 2004; Saari, 2000; Tang et al., 2013).”

“The isomerized 11-cis-retinol is sent back to the cones, where 11-cis-retinol is oxidized to 11-cis-retinal to regenerate visual pigments (3, 5, 6).”

“Regeneration of the pigment is attained by binding of opsin to 11-cis retinal supplied with mechanisms known as the retinoid cycle or the visual cycle (3).”

“…in the retina microenvironment and find the crucial cell type related to AMD, a NaIO 3 - induced mouse model, a well-known drug-induced model of geographic atrophy (advanced dAMD), 16,17,20,21 was established (Figure S1), and single-cell transcriptome analysis was performed 22 (Figure 1A).”

“Relatively low ATR concentrations can induce cellular death (51), so careful control over free ATR is needed due to the immensely high potential concentration of ATR in a photoactivated rod cell (52).”

“outer segment, because the outer segment is not a site for protein synthesis (Young 1976; Tang et al. 2013; Martínez-Navarrete et al. 2007).”

“Макрофаги, присутствующие в вителлиформных отложениях, могут в некоторой степени выполнять функции пигментного эпителия, например осуществлять фагоцитоз отходов жизнедеятельности фоторецепторов [58].”

“[6] Tang PH, Kono M, Koutalos Y et al.”

“the shuttling of 11-cis-retinal to the rod photoreceptor cell from the RPE, where it binds to a protein called opsin to form the visual pigment, rhodopsin.(14,16,17) Absorption of a photon catalyzes the isomerization of 11-cis-retinal to all-trans-retinal and results in its release.”

“All-trans retinal is recycled by one of two pathways, binding to IRBP in the IPM and then diffusing either to the RPE [16] or to Müller cells to feed into the newly described retinal visual cycle [20–23].”

“prosthetic group, trans-retinal, to cis-retinal, part of the classic vertebrate eye visual cycle (Tang et al., 2013).”