Function of mammalian M-cones depends on the level of CRALBP in Muller cells

Cone photoreceptors mediate daytime vision in vertebrates. The rapid and efficient regeneration of their visual pigments following photoactivation is critical for the cones to remain photoresponsive in bright and rapidly changing light conditions. Cone pigment regeneration depends on the recycling of visual chromophore, which takes place via the canonical visual cycle in the retinal pigment epithelium (RPE) and the Muller cell-driven intraretinal visual cycle. The molecular mechanisms that enable the neural retina to regenerate visual chromophore for cones have not been fully elucidated. However, one known component of the two visual cycles is the cellular retinaldehyde-binding protein (CRALBP), which is expressed both in the RPE and in Muller cells. To understand the significance of CRALBP in cone pigment regeneration, we examined the function of cones in mice heterozygous for Rlbp1, the gene encoding CRALBP. We found that CRALBP expression was reduced by similar to 50% in both the RPE and retina of Rlbp1(+/-) mice. Electroretinography (ERG) showed that the dark adaptation of rods and cones is unaltered in Rlbp1(+/-) mice, indicating a normal RPE visual cycle. However, pharmacologic blockade of the RPE visual cycle revealed suppressed cone dark adaptation in Rlbp1(+/-) mice in comparison with controls. We conclude that the expression level of CRALPB specifically in the Muller cells modulates the efficiency of the retina visual cycle. Finally, blocking the RPE visual cycle also suppressed further cone dark adaptation in Rlbp1(-/-) mice, revealing a shunt in the classical RPE visual cycle that bypasses CRALBP and allows partial but unexpectedly rapid cone dark adaptation.

Automated summary

The study reveals the crucial role of cellular retinaldehyde-binding protein (CRALBP) in cone pigment regeneration, especially in modulating the efficiency of the retina visual cycle through its expression in Muller cells. Blocking the RPE visual cycle in mice with reduced CRALBP expression resulted in suppressed cone dark adaptation, indicating a shunt in the classical RPE visual cycle bypasses CRALBP and allows rapid cone dark adaptation.