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Alexander V Kolesnikov, Akiko Maeda, Peter Hao Tang, Yoshikazu Imanishi, Krzysztof Palczewski, Vladimir J Kefalov; Essential Roles of RDH8, ABCA4, and Rods in Modulating Dark Adaptation of Mammalian Cones. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1704.
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© ARVO (1962-2015); The Authors (2016-present)
Rapid recycling of visual chromophore and regeneration of the visual pigment are critical for the function of mammalian cones in daylight. Retinol dehydrogenase 8 (RDH8) and ATP-binding cassette transporter (ABCA4) play important roles in the clearance of chromophore from rods and its recycling by the RPE. However, the role of these proteins in modulating the supply of chromophore to cones and cone dark adaptation is unknown. Another unresolved issue is the identity of enzyme(s) responsible for oxidation of 11-cis-retinol in cones. Finally, the impact of rods on dark adaptation of cones also has not been determined. We sought to address these questions.
The expression of RDH8 and ABCA4 in mouse M-cones was confirmed by IHC. M-cone dark adaptation following a >90% pigment bleach was tested by in vivo ERG and ex vivo transretinal ERG recordings. The recordings were carried out in two-month-old control Gnat1-/- mice lacking rod signaling, Rdh8-/-Gnat1-/- and Abca4-/-Gnat1-/- double knockouts (DKO), and Rdh8-/-Abca4-/-Gnat1-/- triple knockout (TKO) lines. The impact of rods on cone dark adaptation was evaluated in one-month-old Rho-/- animals that retained robust cone function.
Both DKO lines had normal cone responses. However, the RPE-driven (but not the retina-driven) phase of their cone dark adaptation was compromised. In contrast, despite their normal morphology, TKO cones had reduced photoresponse amplitudes. Notably, cone dark adaptation driven by either the retina visual cycle or the RPE visual cycle was suppressed in TKO mice. This delay was caused by two separate mechanisms: a direct involvement of RDH8 and ABCA4 in cone chromophore processing, and an indirect delay in the RPE visual cycle due to slow release of spent chromophore from RDH8/ABCA4-deficient rods. In contrast, cone dark adaptation was accelerated in Rho-/- mice suggesting that under normal conditions competition with rods for recycled chromophore delays cone pigment regeneration. Finally, we found that in contrast to control cones, bleached TKO (but not Abca4-/-Gnat1-/-) cones lacked the ability to dark-adapt by oxidizing exogenous 9-cis-retinol.
Efficient processing of chromophore by RDH8 and ABCA4 is essential for the rapid and complete dark adaptation of mammalian M-cones. RDH8 can contribute to the oxidation of cis-retinoids in cones. Competition with rods modulates the rate of cone dark adaptation.
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