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J. Biol. Chem., Vol. 280, Issue 19, 18822-18832, May 13, 2005
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Role of Photoreceptor-specific Retinol Dehydrogenase in the Retinoid Cycle in Vivo*
From the Departments of aOphthalmology, ePhysiology and Biophysics, gPharmacology, and hChemistry, University of Washington, Seattle, Washington 98195 and the Departments of cOphthalmology and Visual Sciences, fBiology, and dNeurobiology and Anatomy, University of Utah, Salt Lake City, Utah 84112
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.
Received for publication, February 15, 2005 , and in revised form, March 7, 2005.
* This work was supported by National Institutes of Health Grants EY08123, EY08061, EY11850, and EY13385, the Stargardt and Retinal Eye Disease Fund, a grant from James and Jayne Lea, a grant from Research to Prevent Blindness, Inc. to the Dept. of Ophthalmology at the University of Utah, a grant from the Macular Vision Research Foundation, a Center grant from the Foundation Fighting Blindness to the University of Utah, 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.
b Both authors contributed equally to this work.
i 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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