期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 102, 期 23, 页码 8162-8167出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0503318102
关键词
retinal; rhodopsin; vitamin A; electroretinogram; retinal pigment epithelium
资金
- NEI NIH HHS [EY00939, EY13385, R01 EY009339, R01 EY013385] Funding Source: Medline
In vertebrate retinal photoreceptors, photoisomerization of opsin-bound visual chromophore 11-cis-retinal to all-trans-retinal triggers phototransduction events. Regeneration of the chromophore is a critical step in restoring photoreceptors to their dark-adapted state. This regeneration process, called the retinoid cycle, takes place in the photoreceptor outer segments and in the retinal pigmented epithelium (RIPE). We have suggested that the regeneration of the chromophore might occur through a retinyl carbocation intermediate. Here, we provide evidence that isomerization is inhibited by positively charged retinoids, which could act as transition state analogs of the isomerization process. We demonstrate that retinylamine (Ret-NH2) potently and selectively inhibits the isomerization step of the retinoid cycle in vitro and in vivo. Ret-NH2 binds a protein(s) in the RIPE microsomes, but it does not bind RPE65, a protein implicated in the isomerization reaction. Although Ret-NH2 inhibits the regeneration of visual chromophore in rods and, in turn, severely attenuates rod responses, it has a much smaller effect on cone function in mice. Ret-NH2 interacts only at micromolar concentrations with retinoic acid receptor, does not activate retinoid-X receptor, and is not a substrate for CYP26s, the retinoic acid-metabolizing cytochrome P450 enzymes. Ret-NH2 can be a significant investigational tool to study the mechanism of regeneration of visual chromophore.
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