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J. Biol. Chem., Vol. 280, Issue 10, 8694-8704, March 11, 2005

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Delayed Dark Adaptation in 11-cis-Retinol Dehydrogenase-deficient Mice

A ROLE OF RDH11 IN VISUAL PROCESSES IN VIVO^*

Tom S. Kim¶, Akiko Maeda||, Tadao Maeda||, Cynthia Heinlein, Natalia Kedishvili**, Krzysztof Palczewski||¶¶, and Peter S. Nelson

From the Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, the Departments of ^||Ophthalmology, Pharmacology, and Chemistry, University of Washington, Seattle, Washington 98195, and ^**Biochemistry and Molecular Genetics, Schools of Medicine and Dentistry, University of Alabama at Birmingham, Birmingham, Alabama 35294

The oxidation of 11-cis-retinol to 11-cis-retinal in the retinal pigment epithelium (RPE) represents the final step in a metabolic cycle that culminates in visual pigment regeneration. Retinol dehydrogenase 5 (RDH5) is responsible for a majority of the 11-cis-RDH activity in the RPE, but the formation of 11-cis-retinal in rdh5^–/– mice suggests another enzyme(s) is present. We have previously shown that RDH11 is also highly expressed in RPE cells and has dual specificity for both cis- and trans-retinoid substrates. To investigate the role of RDH11 in the retinoid cycle, we generated rdh11^–/– and rdh5^–/–rdh11^–/– mice and examined their electrophysiological responses to various intensities of illumination and during dark adaptation. Retinoid profiles of darkadapted rdh11^–/– mice did not show significant differences compared with wild-type mice, whereas an accumulation of cis-esters was detected in rdh5^–/– and rdh5^–/–rdh11^–/– mice. Following light stimulation, 73% more cis-retinyl esters were stored in rdh5^–/–rdh11^–/– mice compared with rdh5^–/– mice. Single-flash ERGs of rdh11^–/– showed normal responses under dark- and light-adapted conditions, but exhibited delayed dark adaptation following high bleaching levels. Double knockout mice also had normal ERG responses in dark- and light-adapted conditions, but had a further delay in dark adaptation relative to either rdh11^–/– or rdh5^–/– mice. Taken together, these results suggest that RDH11 has a measurable role in regenerating the visual pigment by complementing RDH5 as an 11-cis-RDH in RPE cells, and indicate that an additional unidentified enzyme(s) oxidizes 11-cis-retinol or that an alternative pathway contributes to the retinoid cycle.

Received for publication, November 22, 2004 , and in revised form, December 29, 2004.

^* This research was supported by Grants CA85859 and DK65204 (to P. S. N.) and EY08061 from the National Institutes of Health (to K. P.), a grant from the Stargardt and Retinal Eye Disease Fund, and a grant from the E. K. Bishop Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

^¶ Recipient of a postdoctoral fellowship from the Canadian Institutes for Health Research.

^¶¶ A Research to Prevent Blindness, Inc. (RPB) Senior Investigator. To whom correspondence should be addressed: Dept. of Ophthalmology, University of Washington, Box 356485, Seattle, WA 98195-6485. Tel.: 206-543-9074; Fax: 206-221-6784; E-mail: palczews{at}u.washington.edu.

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