Rod outer segment (ROS) renewal as a mechanism for adaptation to a new intensity environment. II. Rhodopsin synthesis and packing density

doi:10.1016/S0014-4835(95)80055-7

Experimental Eye Research

Volume 61, Issue 1, July 1995, Pages 25-32

https://doi.org/10.1016/S0014-4835(95)80055-7 Get rights and content

Using intraocular injection of a ³H-phe and ³H-leu mixture, we found that the net synthesis of rhodopsin is light-intensity-dependent and can adjust when an animal encounters a new lighting environment. Rhodopsin net synthesis dropped dramatically in day 1, 200-lx immigrants; however, preliminary studies show that the opsin mRNA levels in these animal were the same as that found in the 200-lx-native group. This suggests that the changes in the net synthesis of rhodopsin found when an animal is moved to a higher intensity light may be controlled at some point post-transcriptionally. Microspectrophotometric measurements on single rod cells revealed that the differences in whole-eye rhodopsin levels between the two cyclic intensity groups, 3 lx and 200 lx, were also present at the single cell level. This supports previous studies suggesting that the density of rhodopsin per disc varies according to the intensity of light to which the animal is exposed. Individual rods also had differences in packing density of rhodopsin at the base compared to the tip of the same outer segment when the animal had been switched to a new intensity for one half of a turnover period (5 days). This indicates the amount of rhodopsin per disc is regulated and suggests that renewal is the process responsible for creating a modified outer segment. Animals, when switched to a new intensity, can adjust the synthesis of rhodopsin and the number of molecules added per disk to ensure the appropriate packing density of rhodopsin in the rod outer segment (ROS) disk membranes for that level of light intensity.

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Light regulation of rhodopsin distribution during outer segment renewal in murine rod photoreceptors
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Vision under dim light relies on primary cilia elaborated by rod photoreceptors in the retina. This specialized sensory structure, called the rod outer segment (ROS), comprises hundreds of stacked, membranous discs containing the light-sensitive protein rhodopsin, and the incorporation of new discs into the ROS is essential for maintaining the rod’s health and function. ROS renewal appears to be primarily regulated by extrinsic factors (light); however, results vary depending on different model organisms. We generated two independent transgenic mouse lines where rhodopsin’s fate is tracked by a fluorescently labeled rhodopsin fusion protein (Rho-Timer) and show that rhodopsin incorporation into nascent ROS discs appears to be regulated by both external lighting cues and autonomous retinal clocks. Live-cell imaging of the ROS isolated from mice exposed to six unique lighting conditions demonstrates that ROS formation occurs in a periodic manner in cyclic light, constant darkness, and artificial light/dark cycles. This alternating bright/weak banding of Rho-Timer along the length of the ROS relates to inhomogeneities in rhodopsin density and potential points of structural weakness. In addition, we reveal that prolonged dim ambient light exposure impacts not only the rhodopsin content of new discs but also that of older discs, suggesting a dynamic interchange of material between new and old discs. Furthermore, we show that rhodopsin incorporation into the ROS is greatly altered in two autosomal recessive retinitis pigmentosa mouse models, potentially contributing to the pathogenesis. Our findings provide insights into how extrinsic (light) and intrinsic (retinal clocks and genetic mutation) factors dynamically regulate mammalian ROS renewal.
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Citation Excerpt :
Thus, the RPE65 protein would remain intact, the substrate for generation of visual chromophore (all-trans-retinyl esters) would not be depleted, and intraocular vitamin A deficiency would not arise. Unlike developing photoreceptors, mature photoreceptors demonstrate an intrinsic plasticity that enables their outer segments to adjust the packing density of opsin proteins under conditions of varied light levels and vitamin A status [81]. This adaptive feature of mature photoreceptors ensures functional integrity of the retina under widely varying conditions of light and vitamin A status.
Retinal photoreceptors continually endure stresses associated with prolonged light exposure and the metabolic demands of dark adaptation. Although healthy photoreceptors are able to withstand these stresses for several decades, the disease-affected retina functions at a reduced capacity and is at an increased risk for dysfunction. To alleviate cellular and metabolic stressors in degenerative retinal diseases, a new class of drugs that modulate the metabolic activity of the retina have been developed. A clinical candidate in this class (emixustat) has been shown to reduce retinal pathology in various animal models of human retinal disease and is currently under clinical study. Here, we describe the pharmacological properties of emixustat, its mechanisms of action, and potential for use in the treatment of specific retinal diseases.
Electroretinography in patients with winter seasonal affective disorder
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A retinal sensitivity abnormality has been hypothesized in seasonal affective disorder (SAD). To explore this hypothesis, the electroretinogram (ERG) was used to assess retinal sensitivity at the level of the rod photoreceptor system. We examined 27 depressed patients who met DSM-III-R criteria for major depression, recurrent, with a seasonal (winter) pattern and 23 normal control subjects who were age-paired and sex-matched as much as possible with the SAD patients. ERG testing was performed in dark-adapted, dilated eyes in winter between 10:00 and 15:00 h. Retinal sensitivity was based on the light stimulus intensity necessary to reach a 50-μV amplitude threshold. We found that retinal sensitivity was significantly lower (0.21 log units) in SAD patients compared with normal control subjects and that 55% of the patients had a retinal sensitivity value one standard deviation lower than the mean value of the control subjects. These results are consistent with a retinal hyposensitivity hypothesis for SAD, but the explanation for lower rod photoreceptor sensitivity in SAD is not known. We hypothesize that brain neurotransmitter dysregulation may be at the origin of both the mood disorder and retinal sensitivity change.
Recovery of the rod photoresponse in infant rats
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We tested the hypothesis that the kinetics of recovery of the rod photoresponse differ between mature and immature rods. A paired flash paradigm was used. The effect of a test flash on the ERG a-wave response to a probe flash presented 60 to 2 s after the test flash was studied. The functions summarizing the interaction between the test and probe flash did not differ significantly between infants and adults if the stimuli were equated for estimated proportion of rhodopsin isomerized/rod/flash. The kinetics of rod cell recovery are likely the same in infants and adults.
Electrophysiological evidence suggesting a seasonal modulation of retinal sensitivity in subsyndromal winter depression
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Background: An anomaly in the retinal adaptation processes to the decreased light exposure in winter has been suggested as a contributing factor in winter depression. The purpose of this study was to investigate seasonal variations in rod sensitivity in normal subjects and in subjects with seasonal mood variations. Methods: Nine normal subjects (5 men, 4 women, aged 21–28 years) and 12 subjects with subsyndromal seasonal affective disorder (S-SAD)(3 men, 9 women, aged 21–44 years) were selected based on their global seasonality score (GSS) from the Seasonal Pattern Assessment Questionnaire. Scotopic electroretinograms (ERGs) were obtained once in winter and once in summer. Retinal sensitivity, which represents a relative threshold, was obtained from the rod ERG luminance–response functions. Results: A difference in retinal sensitivity between the two groups appeared only in the winter with lower retinal sensitivity found in the S-SAD group. A positive correlation between the GSS and the magnitude of the winter decrease in rod sensitivity was also observed. Limitations: The S-SAD subjects studied in this research did not receive a formal psychiatric evaluation. This will be necessary in future studies to determine if the changes in retinal sensitivity are specific to seasonal affective disorders. In addition, in the present study, the differences in age and gender between the two groups limit the interpretation of the possible contribution of these two parameters to the results. Conclusion: The seasonal changes in retinal sensitivity that parallel seasonal mood variations suggest that the ERG may represent a useful tool to investigate seasonal affective disorders.
Protection of photoreceptor cells in adult rats from light-induced degeneration by adaptation to bright cyclic light
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Light history has been shown to affect the susceptibility of the albino rat retina to the damaging effects of constant light exposure. Retinas of animals raised in relatively bright cyclic light are protected against light-induced degeneration compared with dim-reared animals. These effects were observed in animals raised from birth in bright cyclic light and are part of an adaptive response that protects photoreceptors from stress-induced degeneration. To determine if retinas of adult animals are capable of such adaptive changes or flexibility by switching between different light environments which do not pathologically damage photoreceptor cells, albino rats were maintained in less than 250 lux cyclic light for more than 3 weeks. At 12–13 weeks of age, they were placed into 800 lux cyclic light for 1 week, after which they were exposed to constant illumination of 1500 lux for 1, 3 or 7 days. Retinal function was evaluated by electroretinography and photoreceptor cell death was quantified by measuring outer nuclear layer thickness. After 1 week in bright cyclic light, the retinas were completely protected against 1 day constant light exposure that significantly damaged retinas of animals without 800 lux cyclic light adaptation. Significant protection was also observed in 3 day constant light exposed animals; limited protection occurred after 7 days exposure. These results indicate that the retinas of adult rats adapted to bright cyclic light within certain ranges that did not significantly damage photoreceptor cells are protected from constant light challenge. This phenomenon is a post-developmental response that demonstrates a remarkable plasticity of the retina. The mechanism(s) underlying the ability of this adaptation/flexibility in protecting photoreceptors could involve endogenous molecules that encompass many aspects of retinal cell and molecular biology and physiology. Identification of these molecules may provide insight into the development of therapeutic approaches to treat retinal degeneration.

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Rod outer segment (ROS) renewal as a mechanism for adaptation to a new intensity environment. II. Rhodopsin synthesis and packing density

Vis. Res.

Exp. Eye Res.

Exp. Eye Res.

Exp. Eye Res.

Meth. Enzym.

J. Biol. Chem.

Cell

Meth. Neurosci.

Exp. Eye Res.

Exp. Eye Res.

Exp. Eye Res.

Exp. Eye Res.

Neuron

Exp. Eye Res.

Exp. Eye Res.

Microspectrophotometric demonstration of four classes of photoreceptor in an old world primate Macaca fasicularis

J. Physiol.

Diurnal expression of transducin mRNA and translocation of transducin in rods of rat retina

Science