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J. Biol. Chem., Vol. 283, Issue 15, 9543-9554, April 11, 2008

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Metabolic Basis of Visual Cycle Inhibition by Retinoid and Nonretinoid Compounds in the Vertebrate Retina^*

Marcin Golczak, Akiko Maeda, Grzegorz Bereta, Tadao Maeda, Philip D. Kiser¹, Silke Hunzelmann, Johannes von Lintig, William S. Blaner^¶, and Krzysztof Palczewski²

From the Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, the Institute of Biology I, Animal Physiology and Neurobiology, Hauptstrasse 1, D-79104 Freiburg, Germany, and the ^¶Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York 10032

In vertebrate retinal photoreceptors, the absorption of light by rhodopsin leads to photoisomerization of 11-cis-retinal to its all-trans isomer. To sustain vision, a metabolic system evolved that recycles all-trans-retinal back to 11-cis-retinal. The importance of this visual (retinoid) cycle is underscored by the fact that mutations in genes encoding visual cycle components induce a wide spectrum of diseases characterized by abnormal levels of specific retinoid cycle intermediates. In addition, intense illumination can produce retinoid cycle by-products that are toxic to the retina. Thus, inhibition of the retinoid cycle has therapeutic potential in physiological and pathological states. Four classes of inhibitors that include retinoid and nonretinoid compounds have been identified. We investigated the modes of action of these inhibitors by using purified visual cycle components and in vivo systems. We report that retinylamine was the most potent and specific inhibitor of the retinoid cycle among the tested compounds and that it targets the retinoid isomerase, RPE65. Hydrophobic primary amines like farnesylamine also showed inhibitory potency but a short duration of action, probably due to rapid metabolism. These compounds also are reactive nucleophiles with potentially high cellular toxicity. We also evaluated the role of a specific protein-mediated mechanism on retinoid cycle inhibitor uptake by the eye. Our results show that retinylamine is transported to and taken up by the eye by retinol-binding protein-independent and retinoic acid-responsive gene product 6-independent mechanisms. Finally, we provide evidence for a crucial role of lecithin: retinol acyltransferase activity in mediating tissue specific absorption and long lasting therapeutic effects of retinoid-based visual cycle inhibitors.

Received for publication, November 1, 2007 , and in revised form, December 20, 2007.

^* This work was supported by National Institutes of Health Grants EY09339 and P30 EY11373. The University of Washington licensed some of the technology described here to Acucela Inc. K. P. is a consultant for Acucela Inc. 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.

¹ Supported by the Visual Science Training Program Grant 2T32EY007157 from the NEI, National Institutes of Health.

² To whom correspondence should be addressed: Dept. of Pharmacology, School of Medicine, Case Western Reserve University, Wood Bldg., 10900 Euclid Ave., Cleveland, OH 44106-4965. E-mail: kxp65{at}case.edu.

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