Deletion of GRK1 Causes Retina Degeneration through a Transducin-Independent Mechanism

Rpe65−/−mice are unable to produce 11-cis-retinal, the chromophore of visual pigments. Consequently, the pigment is present as the apoprotein opsin with a minute level of pigment containing 9-cis-retinal as chromophore. Notably, a 10–20% fraction of this opsin is mono-phosphorylated independently of light conditions. To determine the role of rhodopsin kinase (GRK1) in phosphorylating this opsin and to test whether eliminating this phosphorylation would accelerate photoreceptor degeneration, we generated theRpe65−/−Grk1−/−mouse. The retinae ofRpe65−/−Grk1−/−mice had negligible opsin phosphorylation, extensive degeneration with decreased opsin levels, and diminished light-evoked rod responses relative toRpe65−/−mice. These data show that opsin phosphorylation in theRpe65−/−mouse is due to the action of GRK1 and is neuroprotective. However, despite the higher activity of unphosphorylated opsin, the severe loss of opsin in the rapidly degeneratingRpe65−/−Grk1−/−mice resulted in lower overall opsin activity and in higher rod sensitivity compared withRpe65−/−mice. InRpe65−/−Grk1−/−Gnat1−/−mice where transduction activation was blocked, degeneration was only partially prevented. Therefore, increased opsin activity in the absence of phosphorylation was not the only mechanism for the accelerated retinal degeneration. Finally, the deletion of GRK1 triggered retinal degeneration inGrk1−/−mice after 1 month, even in the absence of apo-opsin. This degeneration was independent of light conditions and occurred even in the absence of transducin inGrk1−/−Gnat1−/−mice. Taken together, our results demonstrate a light-independent mechanism for retinal degeneration in the absence of GRK1, suggesting a second, not previously recognized role for that kinase.