Molecular Vision 2002; 8:455-461 <>
Received 10 October 2002 | Accepted 26 November 2002 | Published 5 December 2002

Epitope masking of rhabdomeric rhodopsin during endocytosis-induced retinal degeneration

Nicholas R. Orem, Patrick J. Dolph

Department of Biological Sciences, Dartmouth College, Hanover, NH

Correspondence to: Patrick J. Dolph, Department of Biological Sciences, Dartmouth College, 6044 Gilman, Hanover, NH, 03755; Phone: (603) 646-1092; FAX: (603) 646-1347; email:


Purpose: To determine the fate of rhodopsin during endocytosis-mediated retinal degeneration.

Methods: Drosophila stocks were raised in complete darkness and shifted to light for 24 h prior to dissection and fixation of retinas. 1 μm frozen sections were cut on an ultracryomicrotome, then stained with antibodies specific for rhodopsin or arrestin. Localization of photoreceptor cell-specific proteins was determined by confocal microscopy.

Results: Flies that are in the process of undergoing endocytosis-mediated retinal degeneration exhibit an apparent loss of rhabdomeric rhodopsin at early times during the degenerative process. Using different immunological agents, genetic backgrounds, and light treatments, we have found that the binding of arrestin to rhodopsin masked the C-terminal monoclonal antibody epitope and resulted in the loss of rhodopsin immunoreactivity. The loss of immunoreactive rhabdomeric rhodopsin only occured when rhodopsin was depleted from the plasma membrane such that it was found within the rhabdomere at stoichiometric levels with arrestin.

Conclusions: When rhodopsin and arrestin are found at equal levels, binding of arrestin to rhodopsin results in the masking of the antibody epitope on the C-terminus of rhodopsin. Since masking can only occur after most of the rhodopsin has been depleted from the rhabdomere, it can be concluded that during endocytosis-induced retinal degeneration, much of the rhodopsin is localized to the cell body in small puncta. These data suggest that rhodopsin is at extremely high local concentrations in the cytoplasm. The data are discussed in the context of a model for photoreceptor cell apoptosis in retinal degenerative disorders.


Retinal degeneration is a very common inherited disorder in humans defined by a large number of genetic loci. One such common retinal disease is Autosomal Dominant Retinitis Pigmentosa (ADRP) which affects 1 in 3,000 people [1,2]. ADRP is typically characterized by night blindness, progressive loss of visual acuity, peripheral visual field loss, and eventual loss of central vision. Recent work in humans has demonstrated that over 30 distinct loci have been linked to the progression of the disease [3-5]. Although mutations have been identified that cause ADRP, the molecular mechanisms that induce photoreceptor cell apoptosis are unknown in almost all cases.

Due to many similarities between the invertebrate and vertebrate visual system, Drosophila melanogaster provides an excellent model system to study the molecular mechanisms responsible for retinal degeneration. Over the years, classical genetic analysis has generated a large number of physiological and behavioral mutations that disrupt the Drosophila visual transduction cascade [6,7]. Interestingly, many of these lead to retinal degeneration, and typically this degeneration is characterized by the apoptotic death of the photoreceptor cells [8,9]. In addition, some of these mutations are in identical molecules to those that are found in human subjects. Detailed genetic, cell biological, molecular, and biochemical analyses of these mutant lines has provided several molecular mechanisms associated with retinal disease. Photoreceptor cell structural defects [10,11], improper trafficking of rhodopsin [12-14], and constitutive activity of the phototransduction cascade [15-17] are examples of mechanisms that have been elucidated for specific mutations in the Drosophila visual system.

The Drosophila eye consists of approximately 800 unit eyes or ommatidia. [18]. Each ommatidium contains eight photoreceptors surrounding a centralized intraommatidial space. Six of the eight photoreceptors in each ommatidium are responsible for the primary optomotor response and express a very abundant blue light sensitive opsin called Rh1 [19,20]. The photoreceptor cells are approximately 100 μm long and are characterized by a collection of approximately 10,000 microvilli that project into the intraommatidial space. This structure, termed a rhabdomere, is where the visual signaling molecules such as arrestin, rhodopsin, and the light-sensitive channels are found.

We and others have described a molecular mechanism associated with photoreceptor cell apoptosis in Drosophila melanogaster [9,21]. In wildtype photoreceptors, binding to the regulatory protein arrestin inactivates activated rhodopsin. Specific mutations in phototransduction components induce the stabilization of this interaction between rhodopsin and arrestin [22]. When complexed to rhodopsin, arrestin recruits the endocytic machinery and the rhodopsin/arrestin complexes are internalized into the cell body via receptor-mediated endocytosis. Once in the cytoplasm, these complexes induce apoptosis by an unknown mechanism. This phenomenon of endocytosis-mediated apoptosis is a novel cell death inducing mechanism that is responsible for the retinal degeneration observed in several Drosophila visual system mutants [9,21].

Previously, we have shown that during endocytosis-mediated retinal degeneration, most of the rhabdomeric arrestin is internalized into the photoreceptor cell body. However, the fate of rhodopsin is not as clear. Immunofluorescence analysis detects very little rhodopsin in the photoreceptor cell whereas western blot analysis clearly demonstrates that wildtype levels of rhodopsin are expressed [23]. Here we use immunological agents and genetic backgrounds to account for all of the rhodopsin in photoreceptor cells. We show that a small amount of rhodopsin still remains in the rhabdomere but is inaccessible to the antibody due to arrestin binding. The rhabdomeric rhodopsin represents only a small fraction of the opsin expressed in the photoreceptor. Most of the rhodopsin resides in small puncta within the cytoplasm suggesting an extremely high, local concentration of rhodopsin.


Drosophila Genetics, Fly Husbandry, Antibodies

All Drosophila melanogaster stocks were in a white (w) background to eliminate screening pigments in the eye. The norpAEE5 lines has been previously described [24,25] and arr25 is a loss-of-function allele induced by ethyl methanesulfonate (EMS) [15]. The white mutant (w1118) is a spontaneous mutation that has been extensively characterized [26]. The Arr2 antibody is a polyclonal antipeptide antibody [15]. The polyclonal Rh1 antibody was generated to a GST fusion construct containing the entire Rh1 coding region and was a gift from Charles Zuker (Howard Hughes Medical Institute, University of California, San Diego, CA). The Rh1 monoclonal antibody recognizes an epitope at the extreme C-terminus of rhodopsin and was obtained from the Developmental Studies Hybridoma Bank, University of Iowa, Iowa City, IA.

Flies were dark reared at room temperature and shifted to room light for either 24 h, to examine endocytosis of rhodopsin, or 0 h in the case of vitamin A deprived flies. Room light was 7.5 μmol/m2/s of visually active radiation (380-710 nm) as detected by a quantum sensor. Vitamin A-deficient food was made, and vitamin A deprived flies were reared as previously described [9].


Flies were dark reared at room temperature and shifted to room light for the indicated time. Blue and orange light treatment was performed on dissected retinas floating in room temperature phosphate-buffered saline (PBS). Blue and orange illumination was produced with a 300 W xenon/mercury lamp (Oriel, Stamford, CT) and 480 nm or 580 nm band pass filter (Oriel), respectively. The eyes were then fixed with 4% paraformaldehyde in PBS. Fixed tissue was rinsed one time with PBS and then infused with 40% sucrose in PBS overnight at 4 °C. The eyes were then frozen and cut into 1-μm-thick sections using a Sorval MT5000 ultra microtome with a RMC CR2000 cryo attachment (RMC Products, Tucson, AZ). Sections were cut with a sample temperature of -28 °C and a knife temperature of -50 °C. The sections were treated with a blocking solution of 1% BSA and 0.1% saponin in PBS (PBS-S) for 15 min at room temperature and then incubated with antibodies against Arr2 and Rh1 at 4 °C overnight. Antibodies were diluted 1:100 in PBS-S. FITC and TRITC conjugated secondary antibodies (Jackson ImmunoResearch, West Grove, PA) were used at 1:100 for 4 h at room temperature. Stained sections were observed with a Leica DMRE confocal laser-scanning microscope (Leica Microsystems, Heidelberg, Germany). All figures were made using Adobe Photoshop 5.5 (Adobe Systems Inc., San Jose, CA). Rhodamine staining is displayed as magenta to be blue-green colorblind compatible; double-staining between rhodamine (magenta) and fluorescein (green) is displayed as white.

Results & Discussion

In flies lacking phospholipase C (norpA mutants), stable complexes between rhodopsin and arrestin persist in the photoreceptor cell membrane. Arr2 recruits the endocytic machinery and rhodopsin and arrestin are internalized into the cell body, eventually resulting in apoptotic cell death of the photoreceptors. Previously we showed that dark reared norpA flies exhibit primarily a rhabdomeric localization of both arrestin and rhodopsin (Figure 1A-C; [23]). However, after 24 h, the arrestin is distributed throughout the cytoplasm with <10% of the immunoreactivity localized to the rhabdomere (Figure 1D). In contrast, the rhodopsin immunoreactivity is completely lost from the rhabdomere and instead the protein is found localized to a punctate staining pattern within the cell body (Figure 1E). In spite of the apparent loss of rhodopsin by immunofluorescence, western blot analysis demonstrates that rhodopsin is present at wildtype levels in norpA flies after 24 h of light exposure [23]. Therefore, there is a paradox in that norpA-mediated endocytosis results in low levels of rhodopsin immunoreactivity in situ, although wildtype levels of rhodopsin are present in the photoreceptor cell. In order to fully understand endocytosis-mediated retinal degeneration, the fate of rhodopsin during the retinal degeneration process must be determined.

One possible model to explain these results is that wildtype levels of rhodopsin are present in the photoreceptor cell, but the protein is masked during the process of norpA-mediated retinal degeneration. Since the antibody used in this study is a monoclonal directed to the C-terminus, it may not recognize rhodopsin when in certain conformations or when rhodopsin interacts with other phototransduction proteins. To test this hypothesis, we made use of a polyclonal antibody to rhodopsin. This antibody was generated to the entire rhodopsin polypeptide and would be predicted to recognize multiple epitopes. Therefore, this polyclonal antisera should not be prone to epitope masking by conformational changes or protein/protein interactions. Although the rhodopsin monoclonal antisera recognizes only cytoplasmic puncta in norpA flies (Figure 1H), the same tissue stained with a rhodopsin polyclonal antibody shows strong rhabdomeric staining of rhodopsin (Figure 1G). The polyclonal antisera also recognizes rhodopsin as punctate cytoplasmic staining, which are identical to the puncta stained by the monoclonal antibody (Figure 1I). This demonstrates that in norpA flies, the epitope on the C-terminus of rhodopsin is masked in the rhabdomere of light-treated norpA flies, and rhabdomeric rhodopsin is present but can only be visualized by the polyclonal antisera.

There are several models to explain the masking of the C-terminal epitope in norpA flies. Masking could be due to a conformational change in rhodopsin or could involve the binding of a regulatory protein to the cytoplasmic C-terminus. To further explore this phenomenon, we investigated this loss of rhabdomeric immunoreactivity as a function of the conformation of rhodopsin. Drosophila opsin does not bleach following activation like vertebrate opsins, but instead, the chromophore is stable and can be photoconverted between the active metarhodopsin form (M) and the inactive (R) form. The R form absorbs a photon of light at 480 nm (blue) and is converted into the active (M) form. The M form can absorb a second photon of light in the 580 nm range (orange) and convert back to the inactive (R) form. Therefore, utilizing the appropriate light regime, we can examine immunoreactivity of both the R and M forms of Rh1. norpA flies were treated with room light for 24 h and just prior to fixation were illuminated with 15 min of either activating blue light or inactivating orange light. Remarkably, rhodopsin is masked only when present in the active or meta form. The labeling of Rh1 in flies treated with blue light looks identical to room light-treated flies (Figure 2B); rhodopsin appears to be absent from the rhabdomere but instead is localized in a punctate staining pattern in the cytoplasm. However, when norpA flies are treated with orange light the rhodopsin is clearly visible in the rhabdomere (Figure 2E). This suggests that in norpA flies, the monoclonal antibody only recognizes rhodopsin when it is in the inactive (R) form, and that the epitope is masked when rhodopsin converts to the active (M) state.

One possible explanation for the masking results is that the monoclonal antibody only recognizes the inactive form of rhodopsin and the light-dependent conformational change in rhodopsin masks the C-terminal epitope. To test this we examined rhodopsin antibody labeling of wildtype flies. Wildtype flies were raised in darkness, shifted to room light for 24 h, and treated with either blue or orange light. Clearly, the monoclonal antibody recognizes rhabdomeric rhodopsin whether it is in the active (M) form or the inactive (R) form (Figure 3B,E). Therefore, the epitope masking of metarhodopsin is not a property of activated rhodopsin itself, but instead is a characteristic of the activated rhodopsin that is generated in norpA mutants.

The light treatment experiments described in figs 2 and 3 also uncover a previously undescribed characteristic of arrestin. Orange light treatment induces the translocation of arrestin from the rhabdomere to the cytoplasm (Figure 2D, Figure 3D); in contrast, blue light treated flies have wholly rhabdomeric arrestin staining (Figure 2A, Figure 3A). This suggests that there is a very rapid light-dependent translocation of arrestin in and out of the rhabdomere. This light-dependent translocation has been previously described for the Trpl Ca++ channel and was suggested to play a role in the light adaptation process of the photoreceptor [27]. We are presently investigating the molecular basis of the light-dependent redistribution of arrestin.

Since metarhodopsin from wildtype flies is recognized by the monoclonal antibody, it is clear that the light-dependent conformational change in rhodopsin is not the sole reason for C-terminal epitope masking. Another possibility is that a protein may be interacting tightly with the M form of rhodopsin and blocking access to the C-terminus. One candidate, arrestin, has been shown in the vertebrate system to directly interact with the C-terminus of rhodopsin [28]. In addition, Drosophila arrestin binds tightly only to the metarhodopsin form and releases after rhodopsin has been photoconverted back to the inactive (R) form [29]. In order to test for the role of arrestin in masking rhodopsin immunoreactivity, we performed immunofluorescence analysis on norpA/arr2 double mutants. If Arr2 is responsible for the masking observed in norpA flies, then it would be predicted that the epitope masking would be eliminated in these double mutants. As previously described, blue light-treated norpA flies exhibit no rhabdomeric rhodopsin immunoreactivity with the Rh1 monoclonal antibody (Figure 4B). However, under the same conditions, in norpA/arr2 flies, the monoclonal antibody recognizes rhabdomeric rhodopsin (Figure 4D). Therefore, the masking of rhodopsin is dependent on the presence of arrestin, and suggests that arrestin is involved in the epitope masking

Since rhodopsin is in five fold excess to arrestin [15], it would not be predicted that arrestin could mask activated rhodopsin in wildtype flies. However, in norpA flies, much of the rhodopsin has been removed from the rhabdomere by receptor-mediated endocytosis. One possible model to explain the epitope masking in norpA flies is that rhodopsin levels have been lowered such that there is a 1:1 stoichiometric balance between rhodopsin and arrestin in the rhabdomere. Therefore, since the rhabdomeric levels of rhodopsin have been depleted, all rhodopsin in the rhabdomere can be complexed with arrestin upon light stimulation. This model would predict that if arrestin levels remain constant and rhodopsin levels are lowered, the same epitope masking phenomenon should occur. Rhodopsin levels can be lowered by starving flies for the chromophore precursor vitamin A. Flies starved for vitamin A produce about 3% of wildtype levels of rhodopsin [30]. As can be seen in Figure 5, depletion of rhodopsin by vitamin A deprivation mimics the epitope masking observed in norpA flies. Wildtype flies depleted for visual pigment show rhabdomeric rhodopsin in the presence of orange light when analyzed by either the monoclonal or polyclonal antisera (Figure 5C,D). However, when flies are illuminated with activating blue light, the C-terminal epitope is masked and no monoclonal immunoreactivity is observed, whereas the polyclonal antibody still recognizes rhabdomeric rhodopsin (Figure 5A,B). Therefore, stoichiometric interactions between rhodopsin and arrestin results in masking of the C-terminus of rhodopsin from antibody labeling.

It is important to note that there is no quantitative information that can be derived from the immunofluorescence analysis. Vitamin A deprived flies express wildtype levels of arrestin and approximately 3-5% of wildtype rhodopsin by immunoblot analysis. However, sections stained and normalized to the amount of arrestin present show no difference in rhabdomeric rhodopsin between wildtype and vitamin A deprived flies (data not shown). This indicates that changes in rhodopsin levels that differ by even as much as 20% cannot be detected by immunofluorescence. Therefore the masking of the C-terminus of rhodopsin by generating near stoichiometric levels of rhodopsin and arrestin is the only way to obtain quantitative information about rhabdomeric rhodopsin levels.

This work demonstrates that when arrestin interacts with rhodopsin, Rh1 is inaccessible to a C-terminal-specific monoclonal antibody. Complete masking of the Rh1 C-terminal epitope only occurs when rhodopsin is in the active, metarhodopsin, form. In addition, it is necessary to reduce rhabdomeric rhodopsin levels by endocytosis or Vitamin A starvation to be stoichiometric with arrestin. Therefore, during norpA-mediated retinal degeneration, rhodopsin is depleted from the microvillar membrane via receptor-mediated endocytosis such that its level is equal to, or lower than, that of rhabdomeric arrestin. Upon light stimulation, arrestin binds all of the rhabdomeric rhodopsin and the C-terminus is inaccessible to the monoclonal antibody. Based on the known stoichiometric ratios between rhodopsin and arrestin, and assuming that there is no additional epitope masking in norpA mutants, more than 80% rhodopsin must be internalized into the cell body after 24 h of light exposure. Therefore, the punctate staining observed in the cytoplasm of norpA flies represents a majority of the photoreceptor cell rhodopsin.

Since in wildtype flies rhodopsin is five times more abundant than arrestin, these data suggest that 80% of the rhodopsin must be internalized via receptor mediated endocytosis for epitope masking to occur. The amount of cytoplasmic rhodopsin could be even higher than 80%, since much of the arrestin is also depleted from the rhabdomere in norpA flies. Therefore, the cytoplasmic puncta observed in norpA flies represents an extremely high local concentration of rhodopsin. Interestingly, several other neurodegenerative disorders such as Alzheimer's, prion disease, Lewy body diseases, and poly-glutamine disorders such as Huntington's and spinocerebellar ataxias, are all characterized by the accumulation of protein aggregates in the cell body [31]. It has been proposed that these protein aggregates may be responsible for the apoptotic cell death of neurons in these disorders. It is tempting to speculate that the programmed cell death induced in certain forms of retinal degeneration, including endocytosis-mediated apoptosis, is due to the accumulation of rhodopsin aggregates. This would provide a novel molecular mechanism involved in photoreceptor cell apoptosis associated with retinal disease.

This work also establishes a powerful immunological tool for the study of rhodopsin/arrestin interactions. We have demonstrated that the commercially available monoclonal antibody to Drosophila rhodopsin can differentiate between two physiological forms of rhodopsin. This reagent will be valuable to researchers studying the rhodopsin arrestin interactions in situ, or investigating the biochemistry of the interaction between the two proteins. The standard antibody for detection of vertebrate rhodopsin is the 1D4 antibody, which also recognizes the extreme C-terminus of rhodopsin. Therefore, it is possible that the vertebrate antibody may also be used as an immunological tool to differentiate between rhodopsin in the arrestin-bound and arrestin-unbound form.

It has previously been suggested that the C-terminus of Drosophila rhodopsin is dispensable for its function. This is in direct contrast to the vertebrate system where the same region is essential for termination of the visual response [32] and arrestin binding [33,34]. However, recently there has been a proposed role for the Drosophila rhodopsin C-terminus in arrestin interaction. It has been shown that deletion of the C-terminus prevents the apoptosis observed in endocytosis-mediated retinal degeneration due to the decreased affinity between arrestin and rhodopsin [9]. In addition, C-terminal deletion mutants also rescue apoptosis associated with defects in rhodopsin phosphatase [35]. One interpretation of these results is that the C-terminus of invertebrate rhodopsin is not absolutely required for arrestin binding but may be important for stable or tight binding to the receptor [9]. Since arrestin obscures antibody interaction with the rhodopsin C-terminus, this work also suggests that the C-terminal portion of rhodopsin is an important interaction site for arrestin.


We thank Charles Zuker and Rama Ranganathan for antibody reagents essential for this study. The confocal microscope used for this study was supported in part by a grant from the NSF (DBI-9970048) to R. D. Sloboda. This work was supported by grants from the National Eye Institute (RO1 EY11534) and the Pew Scholars Program.


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