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From the Departments of Ophthalmology and Biochemistry, University of Washington School of Medicine, Seattle, Washington.
Rods bleached in vivo therefore do not regenerate their visual purple from material within themselves or in the tissues proximal to them, but from the distally placed pigment epithelium: the pigment epithelium functions in the regeneration of visual purple; it exerts a regenerative action on the rods.1
Phototransduction and the visual cycle play complementary roles in vertebrate vision. Phototransduction is initiated by the photoisomerization of 11-cis-retinal bound to opsin and ultimately results in a change in the release of neurotransmitter by photoreceptor cells. The visual cycle restores the product of photoisomerization, all-trans-retinal, to the 11-cis configuration and allows the regeneration of bleached visual pigments (Fig. 1) . The biochemical mechanism of phototransduction has been extensively studied during the past 2 decades, and as a result, the process serves as the paradigm for understanding G-protein–coupled receptors in general. In contrast, molecular understanding of the visual cycle is poorly developed, and many fundamental questions regarding reactions, enzymes, and control mechanisms remain unanswered. Sequences of cDNAs encoding three visual cycle enzymes have been published2 3 4 ; however, molecular information is unavailable for the other three presumed enzymes of the cycle, including retinol isomerase (isomerohydrolase).
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In humans the progress curves for the regain of visual threshold and for the regeneration of visual pigment coincide when displayed on a semi–log plot.6 7 The molecular explanation for this log–linear relationship is not well understood, and the relationship may be fortuitous, but most agree that a photoproduct is responsible for desensitization of the visual system.6 10 11 Although the molecular identity of the desensitizing intermediate(s) remains a matter of active investigation,10 12 13 14 15 16 it is clear that visual cycle reactions are important in determining the steady state level of bleached visual pigment and thus the sensitivity of the retina.
The critical role of the retinal pigment epithelium (RPE) in visual pigment regeneration is apparent from the studies of 19th century investigators who demonstrated that dissected frog retina could regenerate its bleached visual pigment only when in contact with the RPE.1 17 18 19 The reader is referred to Marmor and Martin20 for a depiction of some of their insightful experiments. It is fortunate that the early physiologists used frog eyes for their experiments because rodent eyes do not regenerate their visual pigments when removed from the animal, as will be discussed later. Fifty years later, Wald21 used extraction techniques to show that vitamin A was involved in the visual process and formulated the first modern version of the visual cycle including the participation of the RPE (Fig. 2) .
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Analysis of the Flow of Retinoids in the Mouse Visual Cycle
Dowling22 determined the flow of retinoids in and out of the RPE by analysis of their temporal appearance during prolonged, total bleaching and recovery in the dark. Several fundamental questions remained regarding the flux of the cycle. What step of the cycle determines the rate of visual pigment regeneration? Is there biochemical evidence to suggest that the cycle is regulated? Do the several retinoid-binding proteins that have been characterized in RPE and Müller cells play essential roles in the visual cycle? We addressed these questions by analyzing the composition of visual cycle retinoids during recovery from a flash or from steady illumination. We chose mice as the experimental animals because of the increasing availability of animals with targeted disruption of genes encoding putative visual cycle components.
The Rate-Limiting Step in the Mouse Visual Cycle
Lightly pigmented mice were dark adapted and subjected to either a
flash or to steady illumination that bleached approximately 40% of
their visual pigment. Retinoids were extracted and analyzed before
bleaching (dark adapted) and during the recovery period in the dark.
The high-performance liquid chromatography traces from an experiment
using flash illumination are shown in Figure 5 , and the results are summarized in Figure 6
. Surprisingly, the only retinoid that accumulated in substantial
amounts during the recovery period was
all-trans-retinal.40
In other words, all
processes after reduction of all-trans-retinal were rapid,
including intercellular transport, esterification, isomerization,
oxidation, and conjugation with opsin. This finding led to the
conclusion that reduction of all-trans-retinal by NADPH
determines the rate of entry of retinoid into the visual cycle and
emphasizes the importance of this reaction.
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Flash illumination of animals and humans has been used with great success in a number of experimental situations. However, it could be argued that physiological conditions are more closely approximated with steady illumination. Thus, we thought it important to verify that our observation of the accumulation of all-trans-retinal during recovery from a flash was not an artifact of the illumination conditions. Dark-adapted mice were subjected to illumination from two 60-W fluorescent bulbs (50 foot-candles). Retinoids were extracted and analyzed at various times after onset of the lights and during the recovery period in the dark. Again, all-trans-retinal was the only retinoid that accumulated in substantial amounts during bleaching and recovery. Figure 7 depicts the amount of all-trans-retinal accumulated during steady state bleaching and during recovery in the dark. The constant light resulted in a steady state with approximately 35% of the visual pigment bleached. When the light was turned off, the all-trans-retinal rapidly decayed to the original dark-adapted value. We compared the rate of decay of all-trans-retinal produced by steady illumination with that produced by a flash. Approximately the same amount of visual pigment was bleached in each case. The results, shown in Figure 8 , illustrate that the recovery from steady illumination is approximately 3.5 times more rapid (half-life [t1/2], 5 minutes with constant illumination; t1/2, 17 minutes with flash illumination). Similar results were reported in a study of phosphorylation of rhodopsin.42
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The Block in the Visual Cycle in Excised Mouse Eyes
Dissected frog eyes, which contain preformed
11-cis-retinyl ester in their RPE,23
regenerate
their visual pigment after bleaching.1
17
18
19
20
However,
mouse eyes, with little if any preformed 11-cis-retinyl
ester,40
do not regenerate their visual pigment once
removed from the animal.43
44
What step in the visual
cycle is blocked in excised mouse eyes? The visual cycle, as currently
postulated, does not include any obvious step that requires metabolic
energy except for the ABCR transporter reaction29
(see
Fig. 4
). Formation of the 11-cis configuration is an
endergonic process,45
46
but the energy required for
formation of the hindered 11-cis configuration has been
postulated to come from the hydrolysis of the ester bond of
all-trans-retinyl ester.47
Thus, it would not
be anticipated that depriving an eye of its source of blood would
prevent the formation of 11-cis-retinoids. We addressed this
question by analyzing the composition of visual cycle retinoids in
bleached, excised mouse eyes.44
Eyes were removed from
dark-adapted mice and subjected to constant illumination (Fig. 9A
). 11-cis-Retinal steadily disappeared during the
illumination period. all-trans-Retinal transiently appeared,
and ultimately all-trans-retinol and
all-trans-retinyl ester accumulated. No
11-cis-retinoids were formed. Based on current ideas about
the visual cycle (Fig. 4) , this suggests that the isomerization
reaction is not functional in excised mouse eyes. This block in the
cycle could result from several causes. Perhaps the isomerization
reaction requires metabolic energy (e.g., ATP), contrary to what has
been suggested, and the ATP stores in these excised eyes are rapidly
depleted. In support of this are reports that the electrical responses
of rabbit eyes rapidly decay in the absence of oxygen and
glucose48
and that excised mouse eyes do not regenerate
their visual pigment unless they are perfused with oxygen and
glucose.43
However, it is also possible that changes in
cellular pH, ionic concentrations, or oxidative stress results in
inhibition of the isomerase.
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Reduction of all-trans-retinal requires a source of reducing power, and numerous studies have demonstrated that in the visual cycle this source must be NADPH.49 50 The pentose phosphate pathway (also known as the hexose monophosphate shunt) supplies most of the NADPH in most tissues.51 This pathway is considered to be constitutive in most quiescent cells except in neutrophils where NADPH is required for superoxide production, in adipose tissue where NADPH is used for fatty acid biosynthesis, and in dividing cells that require ribose-P for DNA synthesis. Activation of glucose 6-phosphate dehydrogenase (G6PD), the first enzyme of the pentose phosphate pathway, by epidermal growth factor has been studied in detail in growing cells where it appears to involve release of the enzyme from structural elements within the cell.52 53 Studies of glucose metabolism emphasized that ROSs were capable of producing NADPH through the pentose phosphate pathway in amounts sufficient to account for reduction of all-trans-retinal.54 However, in dark-adapted rabbit and monkey retina, the ratio of NADPH to nicotinamide adenine dinucleotide phosphate (NADP) was reported to be 0.3,55 indicating that the pathway would have to be activated for reduction to occur. In vivo [13C] nuclear magnetic resonance studies of rabbit retina have demonstrated an activation of the pentose phosphate pathway in constant light.56 Perhaps flash illumination does not fully activate the pentose phosphate pathway in normal mouse eyes and not at all in excised mouse eyes.
The Schiff base linking all-trans-retinal and opsin must be hydrolyzed before the retinoid can be reduced to all-trans-retinol. Differences in the rates of reduction in vivo or the absence of reduction in excised eyes could be due to differences in the rates of hydrolysis of the Schiff bases formed with intermediates generated by a flash or constant illumination. Flash illumination is known to result in phosphorylation primarily of ser334 of opsin, whereas constant illumination results in phosphorylation primarily of ser338.42 Complex formation of these differently phosphorylated opsins with arrestin could further affect the rates of hydrolysis of the Schiff base, although our studies of arrestin knockout mice indicate otherwise44 (see following discussion).
It is also possible that NADPH and all-trans-retinal are generated in separate compartments, and an active process must occur to unite them. The rim protein of ROSs57 has recently been identified as a member of the ABC-transporter family (ABCR).58 59 The rate of hydrolysis of ATP by this protein is stimulated by addition of 11-cis- or all-trans-retinal,28 suggesting that one or both of these retinoids are substrates for the transporter. The investigators propose that the function of the protein is to pump all-trans-retinal from inside the disc, where it is generated, to the cytosolic side, where it can be reduced by NADPH. Recent reports of the accumulation of condensation products of phosphatidylethanolamine and retinal in the ABCR knockout mouse suggests that these may be the actual substrates for the transporter.29 Thus, depletion of ATP in excised mouse eyes could prevent the two substrates of the reaction from uniting. However, this explanation seems unlikely to account for the absence of reduction of all-trans-retinal that we have observed in flashed, excised mouse eyes because reduction occurs in the same experimental system with constant illumination (Fig. 9A) . In addition, a normal rate of visual pigment regeneration was observed in ABCR-/- animals, indicating that the visual cycle is not dependent on the transporter.
Finally, it is possible that the enzyme is directly regulated by unknown mechanisms. The lack of structural information about rod RDH considerably hinders further progress in this area.
Blocked Transport of Retinoids in the Visual Cycle
Constant illumination of mouse eyecups immersed in buffer revealed
a third pattern of metabolism. 11-cis-Retinal steadily
disappeared concomitant with a transient increase in the amount of
all-trans-retinal and an eventual accumulation of
all-trans-retinol (Fig. 9C)
. No retinyl esters were
produced. This result suggests that the transport of
all-trans-retinol to the RPE, where LRAT is
localized60
61
did not occur. Examination of the eyecups
at the end of the experiment provides the explanation for this result.
The retinas became detached during the incubation. This somewhat
trivial explanation nonetheless provides information relative to
retinoid transport in detached retinas and illustrates the power of
retinoid analysis in detecting abnormal visual cycle function.
In summary, the metabolic inertness of all-trans-retinal in excised mouse eyes generated by a flash and the differences in the rates of regeneration after flash or steady bleaching point out how poorly we understand the processes by which the visual cycle is controlled. Continued study will lead to a solution to this problem and very likely to enhanced understanding of the control of the visual cycle.
Analysis of the Flow of Retinoids in Knockout Mice
The Visual Cycle in Arrestin-/- Mice
Photoactivated Rho is quenched in a two-step process involving
opsin phosphorylation by rhodopsin kinase62
and binding of
arrestin to phosphorylated opsin.63
Two studies have
suggested that arrestin affects the activity of RDH in ROS
preparations. Direct addition of arrestin to washed, flashed ROS
membranes results in a 40% inhibition of the rate of reduction of
all-trans-retinal,64
whereas we observed
inhibition of RDH in whole ROS preparations (containing rhodopsin
kinase and arrestin) when ATP and guanosine triphosphate were
added.65
We attribute the ATP effect to phosphorylation of
Rho* by rhodopsin kinase, formation of a complex with arrestin,
and a reduction of the accessibility of
all-trans-retinal to RDH. These results led to the
prediction that reduction of all-trans-retinal and
regeneration of visual pigments would be more rapid in a mouse without
functional arrestin than in normal subjects.
To address these possibilities, we examined the composition of retinoids during bleaching and regeneration in arrestin-/- mice. These animals were born and raised in the dark and subjected to flash bleaching followed by a recovery period in the dark. The distribution of visual cycle retinoids observed before and after a flash is very similar to that seen with normal mice (not shown). The recovery of 11-cis-retinal in the dark was slower in arrestin-/- mice than in normal mice (0.6 and 1.1% per minute, respectively; Fig. 10 ). However, the rates of rhodopsin regeneration were similar (0.8% per minute and 1% per minute, respectively).
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The Visual Cycle in IRBP-/- Mice
There is much circumstantial evidence to support a role for IRBP
in the diffusion of retinoids between RPE and photoreceptor cells: 1)
IRBP possesses two or more high-affinity binding sites for
retinoids.66
67
68
69
70
(2) all-trans-Retinol or
11-cis-retinal has been found to be associated with IRBP
purified from dark- or light-adapted retina,
respectively.71
3) IRBP occurs precisely in the
extracellular compartment separating photoreceptor and RPE
cells.36
72
73
4) Photoreceptor cells die in mice with a
targeted disruption of the IRBP gene.74
5) Studies with
cultured RPE cells suggest that IRBP causes the release of
11-cis-retinal, whereas other binding proteins with affinity
for 11-cis-retinal are ineffective.75
76
6)
IRBP efficiently delivers 11-cis-retinal to toad
photoreceptors for rhodopsin regeneration.77
Other evidence argues against an active role for IRBP in retinoid transport: 1) IRBP is a large, cigar-shaped protein (axial ratio >7:1), an unlikely shape for a transport protein.69 78 79 2) Diffusion of all-trans-retinol between populations of vesicles is relatively rapid and inhibited in the presence of IRBP.80
We examined the kinetics of recovery of 11-cis-retinal and of rhodopsin after a flash with IRBP-/- mice.44 IRBP-/- mice were dark adapted and exposed to a flash that bleached approximately 35% of their visual pigment. Animals were killed before the flash (dark adapted) and at various intervals in the dark after the flash. Retinoids were extracted from the posterior poles of the eyes and analyzed by high-performance liquid chromatography. The flash produced an immediate 35% decrease in the amount of 11-cis-retinal and a concomitant, proportional increase in the amount of the photolysis product all-trans-retinal. Recovery in the dark resulted in an increase in the amount of 11-cis-retinal and a corresponding decrease in the amount of all-trans-retinal. Small, transient increases of all-trans-retinol and retinyl ester were observed during the return to the dark-adapted state. The overall pattern strongly resembled that observed with wild-type mice. The recovery kinetics resulting from four experiments with IRBP-/- mice are shown in Figure 10 , along with the recovery curve obtained with wild-type mice. IRBP-/- mice regenerated their 11-cis-retinal at a rate of 0.8% per minute, compared with a value of 1.1% per minute for a mixed population of wild-type mice. The relatively modest difference in rates of recovery suggests that IRBP does not influence the rate of visual pigment regeneration.
The normal turnover rates for visual pigments and retinoid composition in IRBP-/- mice are surprising in view of the wealth of evidence mentioned earlier. However, we have examined only visual cycle retinoids after a modest bleaching of visual pigments. Perhaps abnormal patterns of retinoid metabolism would become apparent with other bleaching regimens. It is apparent that IRBP plays an important role in visual physiology because photoreceptor cells die in its absence.74 IRBP may act as a buffer in the subretinal space, limiting the concentration of free retinoid and preventing oxidative degradation.80 81 Perhaps the results obtained here will direct research toward other potential roles for IRBP in visual physiology.
Perspective
Outstanding Problems
The visual cycle shown in Figure 4
is consistent with the
available evidence regarding the regeneration of rod visual pigments.
However, this model must be regarded as a working hypothesis for
several reasons. First, several "orphan" retinoid-binding
components have been described, and some are likely to be involved in
the visual cycle. For instance, RPE65 must play a major role in
retinoid metabolism, based on the inability of RPE65-/- mice to make
11-cis-retinoids,82
but its function is not
understood at this time. Other proteins such as peropsin83
and RGR opsin84
have amino acid sequences related to that
of opsin. What are their functions? Peropsin has been localized to the
apical plasma membrane of RPE.83
Could it be involved in
the export of 11-cis-retinal from RPE or in the import of
all-trans-retinol from the interphotoreceptor
matrix? Eicosanoids such as prostaglandins are secreted from
cells through a transmembrane protein called the prostaglandin
transporter, which facilitates secretion and uptake of the hydrophobic
signaling molecules.85
There is insufficient information
to draw any conclusions at this time, but the phenotype associated with
knockout mice may provide an answer. Second, the cone visual cycle
differs from the rod visual cycle in several quantitative aspects
(e.g., faster turnover) and perhaps qualitative aspects as well.
Müller cells are known to contain two retinoid-binding proteins
(CRALBP and CRBP)35
36
37
and to perform several
transformations of retinoids in vitro.86
Do Müller
cells contribute to the regeneration of visual pigments? The answers to
these and other fascinating questions await the results of further
experimentation. However, the questions emphasize our rudimentary
understanding of the complex process of visual pigment regeneration.
Why Is the Visual Cycle So Complex?
Two general systems are used for regeneration of bleached visual
pigments. Invertebrates rely on the establishment of photoequilibrium,
in which the first photon absorbed converts
11-cis-retinal to all-trans-retinal (Fig. 11)
. A second photon can then convert all-trans-retinal
back to 11-cis-retinal. At constant levels of
illumination a steady state level of bleached visual pigment is
generated, which is a factor in determining the sensitivity of the
visual system, as has been discussed. Thus, the chromophore does not
dissociate from the opsin to which it is covalently bound and the meta
II species absorbs in the visible range of the spectrum. In contrast,
in vertebrates there is a complicated system involving dissociation of
the chromophore and regeneration of the 11-cis
configuration in a neighboring nurse cell. What are the advantages and
disadvantages of the two systems? The invertebrate system is inherently
more simple and elegant in design. However, the bleaching rate and the
regeneration rate are tied to the photon flux, a feature perhaps
disadvantageous in rapidly changing light conditions. In contrast, the
vertebrate regeneration system is more complex, because it involves the
participation of two different cell types, several enzymes, and
intercellular flow of retinoids. However, the regeneration rate is
independent of the photon flux, allowing relatively rapid restoration
of visual sensitivity even in the dark.
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Visual Cycle Defects and Inherited Retinal Conditions
Mutations in several genes encoding presumptive visual cycle
components have recently been implicated in several inherited retinal
diseases. The roles of ABCR in Stargardt disease94
and of
RPE65 in Leber’s congenital amaurosis95
96
and in other
retinal diseases have been discussed in detail elsewhere and will not
be covered here. Recently, missense mutations in the gene encoding
11-cis-retinol dehydrogenase have been found in patients
with fundus albipunctatus.97
This form of congenital
stationary night blindness results in delayed dark adaptation and
delayed regeneration of visual pigments.98
99
100
CRALBP has several distinguishing characteristics that strongly suggest its participation in the visual process. First, the protein has a high-affinity binding site for either 11-cis-retinal (Kd, 10 nM) or 11-cis-retinol (Kd, 60 nm).101 Second, CRABLP purifies from RPE saturated with 11-cis-retinal and from neural retinal saturated with 11-cis-retinal and 11-cis-retinol,102 retinoids of the visual cycle. Third, in retina, CRALBP is found in Müller and RPE cells.36 The RPE, of course, is the site of intense retinoid metabolism related to the visual cycle. Fourth, CRALBP affects the enzyme activity of four enzymes of the visual cycle in vitro. The binding protein reduces LRAT-mediated esterification of 11-cis-retinol by 90% and modestly stimulates oxidation of 11-cis-retinol by 11-RDH.103 Apo-CRALBP is required for retinol isomerase (isomerohydrolase) activity104 105 and for release of 11-cis-retinol from endogenous 11-cis-retinyl esters by 11-REH.104 The development of CRALBP knockout mice should resolve the question of the role of CRALBP in visual physiology.106
Mutations in the gene encoding CRALBP have been associated with several forms of retinal degeneration. Affected siblings in a consanguineous pedigree segregating for nonsyndromic autosomal recessive retinitis pigmentosa were homozygous for a G4763A nucleotide substitution in the CRALBP gene. Recombinant CRALBP bearing this substitution (R150Q) did not bind 11-cis-retinal in vitro,107 stressing the importance of the retinoid-binding site. Four mutations in the gene encoding CRALBP were found in three unrelated patients with recessively inherited retinitis punctata albescens.108 Twenty patients from seven families with features of retinitis punctata albescens and macular degeneration (Bothnia dystrophy) were homozygous for a missense mutation (R234W) in the CRALBP gene.109 These results suggest that CRALBP plays an important role in visual physiology.
Müller Cells and Cone Visual Pigment Regeneration
The literature contains many intriguing suggestions that the
visual cycle in cones differs from that in rods and that Müller
cells may be involved. Two retinoid-binding proteins,
CRALBP36
and CRBP,5
37
are found in
Müller and RPE cells in retinas from several species. The
presence of CRALBP is particularly intriguing, because the binding
protein, as mentioned above, has been demonstrated to purify from
neural retina as a mixture of complexes with
11-cis-retinol or 11-cis-retinal.102
The
all-trans- and 9-cis-retinoids modulate
many biologic processes110
but
11-cis-retinoids are only known to be involved in the
visual process or in the absorption of light (pineal). Cultured chick
Müller cells take up exogenous all-trans-retinol
and convert it to all-trans- and
11-cis-retinyl palmitate and
11-cis-retinol. The latter retinoid has been found in
the culture medium.86
Although no oxidation to
11-cis-retinal has been observed, other investigators
have noted that isolated amphibian cone cells resensitize with
exogenous 11-cis-retinol, whereas rods require
11-cis-retinal.111
Goldstein noted that the
amplitude of the cone but not the rod early receptor potential reaches
a steady state in illuminated, isolated frog retina and recovers with a
t1/2 of 5 to 6 minutes in the
dark.112
113
114
Thus, it appears that cones can regenerate
their visual pigment in frog retina in the absence of RPE. However, the
interpretation of these provocative studies hinges on the validity of
the demonstration that early receptor potential amplitude is directly
proportional to the amount of unbleached visual
pigment.115
116
Thus, it seems clear that some interesting
retinoid metabolism occurs in Müller cells, and the presence of
11-cis-retinoids strongly suggests that it is related to
the visual cycle.
Conclusion
This is an exciting time in visual cycle research. During the past few years the number of published studies related to visual pigment regeneration has increased dramatically. Some well-established players have been characterized at the molecular level (for instance, cone RDH, 11-RDH, and LRAT), and several other proteins have been shown to play very important roles in the visual cycle (RPE65 and ABCR). Further indication of the sophistication of the cycle has been shown by studies that point out the complexity of a seemingly simple step such as the reduction of all-trans-retinal. We can anticipate the elaboration of further complexities and further medical relevance as investigators obtain the tools and molecular information necessary for precise dissection of individual and integrated steps of the visual cycle.
Acknowledgements
The author thanks, in particular, Lucille Bredberg, John Crabb, Jing Huang, Greg Garwin, Breandan Kennedy, Ann Milam, Maria Nawrot, Kris Palczewski, and Dan Possin, among the many colleagues who contributed to these studies.
Footnotes
Supported in part by National Institutes of Health Grants RO1 EY02317, EY01730, and EY09339 and by unrestricted awards from Research to Prevent Blindness. JCS is a Senior Scientific Investigator of Research to Prevent Blindness.
Submitted for publication August 6, 1999; accepted August 30, 1999.
Commercial relationships policy: N.
Corresponding author: John C. Saari, Department of Ophthalmology, Box 356485, University of Washington, Seattle, WA 98195-6485. jsaari{at}u.washington.edu
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Z. Wu, A. Hasan, T. Liu, D. C. Teller, and J. W. Crabb Identification of CRALBP Ligand Interactions by Photoaffinity Labeling, Hydrogen/Deuterium Exchange, and Structural Modeling J. Biol. Chem., June 25, 2004; 279(26): 27357 - 27364. [Abstract] [Full Text] [PDF]
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M. L. Batten, Y. Imanishi, T. Maeda, D. C. Tu, A. R. Moise, D. Bronson, D. Possin, R. N. Van Gelder, W. Baehr, and K. Palczewski Lecithin-retinol Acyltransferase Is Essential for Accumulation of All-trans-Retinyl Esters in the Eye and in the Liver J. Biol. Chem., March 12, 2004; 279(11): 10422 - 10432. [Abstract] [Full Text] [PDF]
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M. Nawrot, K. West, J. Huang, D. E. Possin, A. Bretscher, J. W. Crabb, and J. C. Saari Cellular Retinaldehyde-Binding Protein Interacts with ERM-Binding Phosphoprotein 50 in Retinal Pigment Epithelium Invest. Ophthalmol. Vis. Sci., February 1, 2004; 45(2): 393 - 401. [Abstract] [Full Text] [PDF]
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H. P. N. Scholl, C. Bellmann, S. S. Dandekar, A. C. Bird, and F. W. Fitzke Photopic and Scotopic Fine Matrix Mapping of Retinal Areas of Increased Fundus Autofluorescence in Patients with Age-Related Maculopathy Invest. Ophthalmol. Vis. Sci., February 1, 2004; 45(2): 574 - 583. [Abstract] [Full Text] [PDF]
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 M. Mori, D. Metzger, S. Picaud, C. Hindelang, M. Simonutti, J. Sahel, P. Chambon, and M. Mark Retinal Dystrophy Resulting from Ablation of RXR{alpha} in the Mouse Retinal Pigment Epithelium Am. J. Pathol., February 1, 2004; 164(2): 701 - 710. [Abstract] [Full Text] [PDF]
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 O. A. R. Mahroo and T. D. Lamb Recovery of the human photopic electroretinogram after bleaching exposures: estimation of pigment regeneration kinetics J. Physiol., January 15, 2004; 554(2): 417 - 437. [Abstract] [Full Text] [PDF]
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 A. C. Ross and R. Zolfaghari Regulation of Hepatic Retinol Metabolism: Perspectives from Studies on Vitamin A Status J. Nutr., January 1, 2004; 134(1): 269S - 275. [Abstract] [Full Text] [PDF]
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N. M. Qtaishat, T. M. Redmond, and D. R. Pepperberg Acute Radiolabeling of Retinoids in Eye Tissues of Normal and Rpe65-Deficient Mice Invest. Ophthalmol. Vis. Sci., April 1, 2003; 44(4): 1435 - 1446. [Abstract] [Full Text] [PDF]
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R. A. Bhatti, S. Yu, A. Boulanger, R. N. Fariss, Y. Guo, S. L. Bernstein, S. Gentleman, and T. M. Redmond Expression of {beta}-Carotene 15,15' Monooxygenase in Retina and RPE-Choroid Invest. Ophthalmol. Vis. Sci., January 1, 2003; 44(1): 44 - 49. [Abstract] [Full Text] [PDF]
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J. C. Saari, M. Nawrot, G. G. Garwin, M. J. Kennedy, J. B. Hurley, N. B. Ghyselinck, and P. Chambon Analysis of the Visual Cycle in Cellular Retinol-Binding Protein Type I (CRBPI) Knockout Mice Invest. Ophthalmol. Vis. Sci., June 1, 2002; 43(6): 1730 - 1735. [Abstract] [Full Text] [PDF]
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J. J Kang Derwent, N. M Qtaishat, and D. R Pepperberg Excitation and desensitization of mouse rod photoreceptors in vivo following bright adapting light J. Physiol., May 15, 2002; 541(1): 201 - 218. [Abstract] [Full Text] [PDF]
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M. Yang and H. K. W. Fong Synthesis of the All-trans-retinal Chromophore of Retinal G Protein-coupled Receptor Opsin in Cultured Pigment Epithelial Cells J. Biol. Chem., January 25, 2002; 277(5): 3318 - 3324. [Abstract] [Full Text] [PDF]
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T. Sakai, G. P. Lewis, K. A. Linberg, and S. K. Fisher The Ability of Hyperoxia to Limit the Effects of Experimental Detachment in Cone-Dominated Retina Invest. Ophthalmol. Vis. Sci., December 1, 2001; 42(13): 3264 - 3273. [Abstract] [Full Text] [PDF]
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S. T. Menon, M. Han, and T. P. Sakmar Rhodopsin: Structural Basis of Molecular Physiology Physiol Rev, October 1, 2001; 81(4): 1659 - 1688. [Abstract] [Full Text] [PDF]
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 A. Wenzel, C. E. Reme, T. P. Williams, F. Hafezi, and C. Grimm The Rpe65 Leu450Met Variation Increases Retinal Resistance Against Light-Induced Degeneration by Slowing Rhodopsin Regeneration J. Neurosci., January 1, 2001; 21(1): 53 - 58. [Abstract] [Full Text] [PDF]
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C. Grimm, C. E. Remé, P. O. Rol, and T. P. Williams Blue Light's Effects on Rhodopsin: Photoreversal of Bleaching in Living Rat Eyes Invest. Ophthalmol. Vis. Sci., November 1, 2000; 41(12): 3984 - 3990. [Abstract] [Full Text]
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C. A. Curcio, C. Owsley, and G. R. Jackson Spare the Rods, Save the Cones in Aging and Age-related Maculopathy Invest. Ophthalmol. Vis. Sci., July 1, 2000; 41(8): 2015 - 2018. [Full Text]
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A. Boulanger, S. Liu, A. A. Henningsgaard, S. Yu, and T. M. Redmond The Upstream Region of the Rpe65 Gene Confers Retinal Pigment Epithelium-specific Expression in Vivo and in Vitro and Contains Critical Octamer and E-box Binding Sites J. Biol. Chem., September 29, 2000; 275(40): 31274 - 31282. [Abstract] [Full Text] [PDF]
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T. M. Redmond, S. Gentleman, T. Duncan, S. Yu, B. Wiggert, E. Gantt, and F. X. Cunningham Jr. Identification, Expression, and Substrate Specificity of a Mammalian beta -Carotene 15,15'-Dioxygenase J. Biol. Chem., February 23, 2001; 276(9): 6560 - 6565. [Abstract] [Full Text] [PDF]
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P. Chen, T. D. Lee, and H. K. W. Fong Interaction of 11-cis-Retinol Dehydrogenase with the Chromophore of Retinal G Protein-coupled Receptor Opsin J. Biol. Chem., June 8, 2001; 276(24): 21098 - 21104. [Abstract] [Full Text] [PDF]
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| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
) 11-cis-Retinal; (•)
all-trans-retinal; (
)
all-trans-retinol; (
) 11-cis-retinol.
Arrow: a flash. Retinyl esters did not change
significantly with this amount of bleaching (not shown). Modified, with
permission, from Palczewski K, Van Hooser JP, Garwin GG, Saari JC.
Kinetics of visual pigment regeneration in excised mouse eyes and in
mice with a targeted disruption of the gene encoding interphotoreceptor
retinoid-binding protein or arrestin. Biochemistry.
1999;39:12012–12019. American Chemical Society.
