Role of Photoreceptor-specific Retinol Dehydrogenase in the Retinoid Cycle in Vivo

Akiko Maeda,Tadao Maeda,Yoshikazu Imanishi,Vladimir Kuksa,Andrei Alekseev,J Darin Bronson,Houbin Zhang,Li Zhu,Wenyu Sun,David A Saperstein,Fred Rieke,Wolfgang Baehr,Krzysztof Palczewski

doi:10.1074/jbc.m501757200

Akiko Maeda, Tadao Maeda + Show 11 more

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https://doi.org/10.1074/jbc.m501757200

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Abstract

The retinoid cycle is a recycling system that replenishes the 11-cis-retinal chromophore of rhodopsin and cone pigments. Photoreceptor-specific retinol dehydrogenase (prRDH) catalyzes reduction of all-trans-retinal to all-trans-retinol and is thought to be a key enzyme in the retinoid cycle. We disrupted mouse prRDH (human gene symbol RDH8) gene expression by targeted recombination and generated a homozygous prRDH knock-out (prRDH-/-) mouse. Histological analysis and electron microscopy of retinas from 6- to 8-week-old prRDH-/- mice revealed no structural differences of the photoreceptors or inner retina. For brief light exposure, absence of prRDH did not affect the rate of 11-cis-retinal regeneration or the decay of Meta II, the activated form of rhodopsin. Absence of prRDH, however, caused significant accumulation of all-trans-retinal following exposure to bright lights and delayed recovery of rod function as measured by electroretinograms and single cell recordings. Retention of all-trans-retinal resulted in slight overproduction of A2E, a condensation product of all-trans-retinal and phosphatidylethanolamine. We conclude that prRDH is an enzyme that catalyzes reduction of all-trans-retinal in the rod outer segment, most noticeably at higher light intensities and prolonged illumination, but is not an essential enzyme of the retinoid cycle.

Highlights

Reduction and oxidation of retinoids are key reactions of the retinoid cycle, which is critical for the production of the chromophore of rhodopsin, 11-cis-retinal (1, 2)
Our data support an auxiliary role for this enzyme in the retinoid cycle and reveal new evidence for an alternative RDH(s) that produces alltrans-retinol from all-trans-retinal in photoreceptor outer segments released from photoactivated rhodopsin and compensates for the lack of Photoreceptor-specific retinol dehydrogenase (prRDH)
To delineate the role of prRDH (RDH8) in the retinoid cycle, we generated a knock-out mouse in which exons 2– 4 of the mouse prRDH gene were deleted by targeted recombination

Summary

Introduction

Reduction and oxidation of retinoids are key reactions of the retinoid cycle (visual cycle), which is critical for the production of the chromophore of rhodopsin, 11-cis-retinal (1, 2). The NADPH-dependent reduction of all-trans-retinal in photoreceptor outer segments is the first step in the regeneration of bleached visual pigment. Several all-trans-retinol dehydrogenases (RDHs) from the photoreceptor cells have been identified. The authors suggested that prRDH is the enzyme responsible for the reduction of all-trans-retinal to all-trans-retinol within the photoreceptor outer segment. All-trans-retinal might form complexes with opsins that activate G protein persistently and cause desensitization of photoreceptor cells (22–26) (reviewed in Ref. 27). Our data support an auxiliary role for this enzyme in the retinoid cycle and reveal new evidence for an alternative RDH(s) that produces alltrans-retinol from all-trans-retinal in photoreceptor outer segments released from photoactivated rhodopsin and compensates for the lack of prRDH

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