Indeed, in addition to reduced or absent phosphorylation due to the loss of functional GRK1, abnormally high phosphorylation of rhodopsin has also been linked to retinal degeneration. For instance, the suppression of rhodopsin dephosphorylation by rdgC in
Drosophila causes extensive light-dependent retinal degeneration.
35 Similarly, enhanced rhodopsin phosphorylation caused by overexpression of GRK1 in transgenic mice also increases the susceptibility of rods to degeneration.
36 A possible link between rhodopsin hyperphosphorylation and retinal degeneration also has been suggested in RCS rats
37 and rhodopsin dephosphorylation is dramatically delayed in P23H rats, with phosphorylated P23H-rhodopsin persisting days after exposure to light.
38 Our results presented here clearly show that the deletion of PP2A accelerates rod degeneration in
Grk1−/− mice. However, the mechanism of this modulation is not likely to involve rhodopsin, as this protein is not phosphorylated in this line,
3 thus eliminating the need for dephosphorylation. Instead, the blockade of catalytic activity of PP2A is likely to exert its effect on exacerbating rod degeneration by suppressing the dephosphorylation of other, yet unidentified, proteins in the rods. One such potential target is phosducin, an abundant rod phosphoprotein that is likely dephosphorylated by PP2A in a light-dependent manner.
20,39 Normally, phosducin is phosphorylated in darkness and dephosphorylated in light. However, in
rd1 mice, a model of retinitis pigmentosa, phosducin is persistently phosphorylated regardless of light conditions.
40 Interestingly, the increased phosducin phosphorylation in
rd1 mice coincided with increased activation of calcium/calmodulin-activated kinase II, possibly representing an early step in photoreceptor degeneration. As phosducin has been suggested to be dephosphorylated by PP2A, it would be expected that deletion of PP2A would also result in increased phosducin phosphorylation. This, combined with the cellular stress caused by the persistent transduction activation in
Grk1−/− and
Arr1−/− mice might explain the accelerated retinal degeneration in these mice caused by the deletion of PP2A. Although the role of phosducin remains to be demonstrated, the increased degeneration in GRK1-deficient rods induced by the deletion of PP2A-Cα indicates a novel rhodopsin phosphorylation-independent mechanism for modulating retinal degeneration, which could be better elucidated by follow-up studies utilizing advanced phosphoproteomic methods and analyses.