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S. Kolandaivelu, B. Chang, V. Ramamurthy; Rod PDE6 Restores Cone Function in Mice Lacking Cone PDE6. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1107.
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The heterotetrameric phosphodiesterase (PDE6) is a crucial enzyme needed for phototransduction and in survival of retinal photoreceptor cells. Rod and cone photoreceptors contain a discrete set of PDE6 proteins that couple to their respective transducin subunits. While the PDE6 subunits are homologous, there are distinct structural differences between the rod and cone PDE6 subunits. This study explores the role that these structural differences may play in light-dependent signaling in cone photoreceptor cells.
For this study, we utilized cone dominated Nrl-mutant mice. In this mouse model, there is a residual expression of rod PDE6. To remove the cone PDE6 subunits from Nrl-mutant mice, we generated a double mutant of Nrl and Cpfl1. In addition, we also generated a triple mutant that removes both the rod and cone PDE subunits (Nrl Cpfl rd). Electroretinogram (ERG) studies were carried out to evaluate both the S and M-cone photopic responses. Differences in retinal morphology were analyzed by immunocytochemistry with known photoreceptor markers. Western blotting was used to detect changes in levels of various proteins that play a role in phototransduction.
Despite removal of cone PDE6 in an all cone mouse model (Nrl-/-Cpfl1-/-), cone photoreceptors show a robust light dependent photopic ERG response. This response was observed exclusively from S-cones. In contrast, M-cones did not respond in the absence of cone PDE6. Consistent with this observation, in adult mice, except for periphery, we did not observe any M-opsin expressing cone cells. Careful biochemical characterization of this mouse model suggests that rod PDE6 is expressed in the absence of cone PDE6. To investigate if the light dependent electrical activity in this double mutant is due to rod PDE6 expression, we generated a triple knockout lacking both PDE6 subunits. In these mice, there is no observable ERG suggesting that rod PDE6 was responsible for signaling. In these mouse models, robust expression of cone transducin was observed.
Our results demonstrate that rod PDE6 can substitute cone PDE6 in cone photoreceptor cells. Our results also imply that cone transducin can couple with rod PDE6 to restore cone function.
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