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Structural and functional impairment of endocytic pathways by retinitis pigmentosa mutant rhodopsin-arrestin complexes
Jen-Zen Chuang, … , Wenjin Jun, Ching-Hwa Sung
Jen-Zen Chuang, … , Wenjin Jun, Ching-Hwa Sung
Published July 1, 2004
Citation Information: J Clin Invest. 2004;114(1):131-140. https://doi.org/10.1172/JCI21136.
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Article Neuroscience

Structural and functional impairment of endocytic pathways by retinitis pigmentosa mutant rhodopsin-arrestin complexes

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Abstract

Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous degenerative eye disease. Mutations at Arg135 of rhodopsin are associated with a severe form of autosomal dominant RP. This report presents evidence that Arg135 mutant rhodopsins (e.g., R135L, R135G, and R135W) are hyperphosphorylated and bind with high affinity to visual arrestin. Mutant rhodopsin recruits the cytosolic arrestin to the plasma membrane, and the rhodopsin-arrestin complex is internalized into the endocytic pathway. Furthermore, the rhodopsin-arrestin complexes alter the morphology of endosomal compartments and severely damage receptor-mediated endocytic functions. The biochemical and cellular defects of Arg135 mutant rhodopsins are distinct from those previously described for class I and class II RP mutations, and, hence, we propose that they be named class III. Impaired endocytic activity may underlie the pathogenesis of RP caused by class III rhodopsin mutations.

Authors

Jen-Zen Chuang, Carrie Vega, Wenjin Jun, Ching-Hwa Sung

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Figure 4

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Endogenous v-arr was mislocalized in rodent rods that expressed R135L bu...
Endogenous v-arr was mislocalized in rodent rods that expressed R135L but not WT or Q344ter rhodopsin. (A) The schematic illustration shows the in vivo electroporation technique. Plasmid is injected into the subretinal space followed by electroporation. Tweezer-type electrodes are placed across the eye, with the anode facing the cornea. (B) A schematic illustration of the bicistronic expression vector pCAG-rhodopsin-IRES-GFP. These vectors permit both rhodopsin and GFP to be translated from a single mRNA and simultaneously expressed in the transfected cells. (C–H) Retinas were transfected with either pCAG-WT-IRES-GFP (C and D), pCAG-Q344ter-IRES-GFP (E and F), or pCAG-R135L-IRES-GFP (G and H). These retinas were immunolabeled with the antibodies indicated, followed by Alexa 594–conjugated secondary antibodies. Representative optical images of photoreceptor layer show transfected rhodopsin immunolabeling (C, E, and G). The GFP signals were directly visualized and are shown in the merge images in (D, F, and H). Note that mAb 3A6 effectively detected the WT but not the R135L mutant in transfected cells. (I–N) Retina sections prepared from eyes transfected with pCAG-WT-IRES-GFP (I and J), pCAG-Q344ter-IRES-GFP (K and L), and pCAG-R135L-GFP (M and N) were immunolabeled with anti–v-arr antibody (red). Representative confocal images of v-arr labeling (I, K, and M) and merge views with GFP+- transfected cells are shown (J, L, and N). The PM (arrow and arrowhead) and the intracellular vacuole accumulation of v-arr (open arrow) are marked. OS, outer segment; IS, inner segment; ONL, outer nuclear layer; OPL, outer plexiform layer. Scale bars: 20 μm.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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