In direct contrast, the phenotype in the model characterised here, with a greater impact on cones than on rods, is likely to be a direct consequence of the point mutation in GCAP1. A role for GCAP1 in phototransduction in both rods and cones is indicated by various studies of GCAP knock-out mice. Mice with a double GCAP1 and GCAP2 knock-out show an altered response of rods to saturating flashes of light which is not rescued by the production of GCAP2 from a transgene, whereas the degree of recovery post-flash in rods and cones has been shown to correlate with the level of GCAP1 expression in these mice when expressing a GCAP1 transgene. GCAP2 is also capable of regulating cGMP production by retGC1 in a Ca2+ -dependent manner. Since GCAP2 is predominantly expressed in rods, the loss of Ca2+ -sensitivity due to the E155G mutation in GCAP1 may be compensated for by GCAP2 to a greater extent in rods than in cones, and may thereby account for the increased loss of cones compared with rods in both the animal model and human disease. In contrast, as shown by the GCAP1 and GCAP2 double knock-out, the loss of all GCAP function does not result in retinal degeneration. The causal relationship between photoreceptor degeneration and mutant GCAP1 has yet to be fully established. Dabrafenib Previous work with transgenic mice expressing mutant GCAP1 protein has shown elevated levels of intracellular Ca2+. This is also the predicted consequence of the elevated cGMP levels seen in the Guca1aCOD3 mutant mice. Elevated levels of Ca2+ have been shown to activate Foretinib apoptotic pathways in rod photoreceptors and may therefore be the major factor in the retinal degeneration in these mice, and in the human disease. The same may be the case in rd1 mutant mice which either lack or have severely reduced levels of the cGMP-phosphodiesterase. It has also been reported in one study that D-cis-diltiazem, a calcium-channel blocker, rescues photoreceptors and preserves visual function in these mice although other studies have failed to confirm these findings. Both heterozygous and homozygous Guca1aCOD3 mutant mice showed a significant delay in the recovery of the rod ERG a-wave after a bright conditioning flash. In vitro, mutant E155G GCAP1 results in a reduced sensitivity of cyclase activity to Ca2+ inhibition, and the elevated levels of cGMP seen in the retinae of the Guca1aCOD3 mutant mice indicate that the mutant GCAP1 is having a similar effect in vivo, so the delay in recovery is presumably a consequence of these elevated levels of cGMP. A delay in recovery of the rod a-wave is also seen in mice lacking both GCAP1 and GCAP2. This delay was reversed by the expression of GCAP1 via a transgene in a dose-dependent manner, and the same was found for the delay in the cone response.