Dataset Information

Positively charged retinoids are potent and selective inhibitors of the trans-cis isomerization in the retinoid (visual) cycle.

ABSTRACT: 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 (RPE). 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 RPE 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.

SUBMITTER: Golczak M

PROVIDER: S-EPMC1149451 | biostudies-literature | 2005 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Positively charged retinoids are potent and selective inhibitors of the trans-cis isomerization in the retinoid (visual) cycle.

Golczak Marcin M Kuksa Vladimir V Maeda Tadao T Moise Alexander R AR Palczewski Krzysztof K

Proceedings of the National Academy of Sciences of the United States of America 20050525 23

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 (RPE). We have suggested that the regeneration of the chromophore might occur through a ...[more]

PMID: 15917330

Similar Datasets

Project description:In order to maintain visual sensitivity at all light levels, the vertebrate eye possesses a mechanism to regenerate the visual pigment chromophore 11-cis retinal in the dark enzymatically, unlike in all other taxa, which rely on photoisomerization. This mechanism is termed the visual cycle and is localized to the retinal pigment epithelium (RPE), a support layer of the neural retina. Speculation has long revolved around whether more primitive chordates, such as tunicates and cephalochordates, anticipated this feature. The two key enzymes of the visual cycle are RPE65, the visual cycle all-trans retinyl ester isomerohydrolase, and lecithin:retinol acyltransferase (LRAT), which generates RPE65's substrate. We hypothesized that the origin of the vertebrate visual cycle is directly connected to an ancestral carotenoid oxygenase acquiring a new retinyl ester isomerohydrolase function. Our phylogenetic analyses of the RPE65/BCMO and N1pC/P60 (LRAT) superfamilies show that neither RPE65 nor LRAT orthologs occur in tunicates (Ciona) or cephalochordates (Branchiostoma), but occur in Petromyzon marinus (Sea Lamprey), a jawless vertebrate. The closest homologs to RPE65 in Ciona and Branchiostoma lacked predicted functionally diverged residues found in all authentic RPE65s, but lamprey RPE65 contained all of them. We cloned RPE65 and LRATb cDNAs from lamprey RPE and demonstrated appropriate enzymatic activities. We show that Ciona ß-carotene monooxygenase a (BCMOa) (previously annotated as an RPE65) has carotenoid oxygenase cleavage activity but not RPE65 activity. We verified the presence of RPE65 in lamprey RPE by immunofluorescence microscopy, immunoblot and mass spectrometry. On the basis of these data we conclude that the crucial transition from the typical carotenoid double bond cleavage functionality (BCMO) to the isomerohydrolase functionality (RPE65), coupled with the origin of LRAT, occurred subsequent to divergence of the more primitive chordates (tunicates, etc.) in the last common ancestor of the jawless and jawed vertebrates.

Dataset Information

Positively charged retinoids are potent and selective inhibitors of the trans-cis isomerization in the retinoid (visual) cycle.

Publications

Positively charged retinoids are potent and selective inhibitors of the trans-cis isomerization in the retinoid (visual) cycle.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets