Synthesis and characterization of a novel retinylamine analog inhibitor of constitutively active rhodopsin mutants found in patients with autosomal dominant retinitis pigmentosa

Snider, Barry B.; Oprian, Daniel D.

doi:10.1073/pnas.94.25.13559

Cited by 15 publications

(10 citation statements)

References 34 publications

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“…As expected, the K296E mutant activates transducin in the absence of light (Chen, Shi, Concepcion, Xie, & Oprian, 2006; Li, Franson, Gordon, Berson, & Dryja, 1995; Moaven et al, 2013; Robinson et al, 1992; Yang et al, 1997). The constitutive activity in K296E opsin and the mechanism by which it causes retinal degeneration, however, are different from that of wild-type opsin.…”

Section: Constitutive Activty In Rhodopsin That Causes Diseasesupporting

confidence: 77%

“…Patients with the K296E mutation in rhodopsin exhibit a severe retinal degeneration with rapid onset (Keen et al, 1991). The in vitro properties of the K296M mutant are similar to those of the K296E mutant (Rim & Oprian, 1995; Yang, Snider, & Oprian, 1997). Thus, both of these mutants may cause disease by similar mechanisms.…”

Section: Constitutive Activty In Rhodopsin That Causes Diseasementioning

confidence: 66%

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Constitutively Active Rhodopsin and Retinal Disease

Park

2014

Advances in Pharmacology

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Rhodopsin is the light receptor in rod photoreceptor cells of the retina that initiates scotopic vision. In the dark, rhodopsin is bound to the chromophore 11-cis retinal, which locks the receptor in an inactive state. The maintenance of an inactive rhodopsin in the dark is critical for rod photoreceptor cells to remain highly sensitive. Perturbations by mutation or absence of 11-cis retinal can cause rhodopsin to become constitutively active, which leads to the desensitization of photoreceptor cells and, in some instances, retinal degeneration. Constitutive activity can arise in rhodopsin by various mechanisms and can cause a variety of inherited retinal diseases including Leber congenital amaurosis, congenital night blindness, and retinitis pigmentosa. In this review, the molecular and structural properties of different constitutively active forms of rhodopsin are overviewed and the possibility that constitutive activity can arise from different active-state conformations is discussed.

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Section: Constitutive Activty In Rhodopsin That Causes Diseasesupporting

confidence: 77%

Section: Constitutive Activty In Rhodopsin That Causes Diseasementioning

confidence: 66%

Constitutively Active Rhodopsin and Retinal Disease

Park

2014

Advances in Pharmacology

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“…Gene delivery is one method of correcting haploinsufficiency. Constitutive activity has been successfully blocked by reverse agonist-like compounds (42,43), and conformation and function can be rescued by small chemical agents (38). The medically most prevalent forms of dominant disorders are the protein conformational disorders.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Chaperone-mediated in Vivo Folding and Stabilization of the P23H-opsin Mutant Associated with Autosomal Dominant Retinitis Pigmentosa

Noorwez¹,

Kuksa²,

Imanishi³

et al. 2003

Journal of Biological Chemistry

187

159

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Protein conformational disorders, which include certain types of retinitis pigmentosa, are a set of inherited human diseases in which mutant proteins are misfolded and often aggregated. Many opsin mutants associated with retinitis pigmentosa, the most common being P23H, are misfolded and retained within the cell. Here, we describe a pharmacological chaperone, 11-cis-7-ring retinal, that quantitatively induces the in vivo folding of P23H-opsin. The rescued protein forms pigment, acquires mature glycosylation, and is transported to the cell surface. Additionally, we determined the temperature stability of the rescued protein as well as the reactivity of the retinal-opsin Schiff base to hydroxylamine. Our study unveils novel properties of P23H-opsin and its interaction with the chromophore. These properties suggest that 11-cis-7-ring retinal may be a useful therapeutic agent for the rescue of P23H-opsin and the prevention of retinal degeneration.

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“…Typically, two mouse eyes were used per assay, and the assays were repeated three to six times. Retinylamine (Ret-NH 2 ) was synthesized by the method described previously (33). Oral gavage was carried out as described previously (31,34).…”

Section: Retinoids: Analyses Synthesis and Treatmentsmentioning

confidence: 99%

Aberrant Metabolites in Mouse Models of Congenital Blinding Diseases: Formation and Storage of Retinyl Esters

Maeda

Imanishi

et al. 2006

Biochemistry

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Regeneration of the visual chromophore, 11-cis-retinal, is a critical step in restoring photoreceptors to their dark-adapted conditions. This regeneration process, called the retinoid cycle, takes place in the photoreceptor outer segments and the retinal pigment epithelium (RPE). Disabling mutations in nearly all of the retinoid cycle genes are linked to human conditions that cause congenital or progressive defects in vision. Several mouse models with disrupted genes related to this cycle contain abnormal fatty acid retinyl ester levels in the RPE. To investigate the mechanisms of retinyl ester accumulation, we generated single or double knockout mice lacking retinoid cycle genes. Alltrans-retinyl esters accumulated in mice lacking RPE65, but they are reduced in double knockout mice also lacking opsin, suggesting a connection between visual pigment regeneration and the retinoid cycle. Only Rdh5-deficient mice accumulate cis-retinyl esters, regardless of the simultaneous disruption of RPE65, opsin, and prRDH. 13-cis-Retinoids are produced at higher levels when the flow of retinoid through the cycle was increased, and these esters are stored in specific structures called retinosomes. Most importantly, retinylamine, a specific and effective inhibitor of the 11-cisretinol formation, also inhibits the production of 13-cis-retinyl esters. The data presented here support the idea that 13-cis-retinyl esters are formed through an aberrant enzymatic isomerization process.Vitamin A transformations in the eye are essential for vision. Absorption of light by the vitamin A-derived chromophore of visual pigments, 11-cis-retinal, leads to its photoisomerization to all-trans-retinal and the initiation of the signal transduction cascade (1-4). Through a chain of reactions, all-trans-retinal is recycled enzymatically back to 11-cis-retinal (5-8). These retinoid cycle reactions (Figure 1) take place in the outer segments of photoreceptor cells and in the adjacent retinal pigment epithelium (RPE). 1 Characterization of the knockout mice lacking genes involved in the retinoid cycle provides important insight into the flow of retinoids in the eye.11-cis-Retinol dehydrogenase (RDH), also known as RDH5, catalyzes the final oxidation reaction of 11-cis-retinol in the RPE (9, 10). Although RDH5 is responsible for the majority of 11-cis-RDH activity, RDH11 and other RDHs also have a measurable role in regenerating the visual pigment by complementing RDH5 in RPE cells (11). Disruption of the gene encoding RDH5 causes fundus albipunctatus in humans (12,13). Fundus albipunctatus is an autosomal recessive form of congenital stationary night blindness characterized by the appearance of numerous small white dots located in the RPE, a delayed course of dark adaptation, and † This research was supported by NIH Grant EY09339. Lipid droplet-like organelles known as retinosomes were characterized as specific sites of alltrans-retinyl ester accumulation in the RPE (19,20). All-trans-retinyl esters accumulate in the RPE of wild-type mice as the...

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Synthesis and characterization of a novel retinylamine analog inhibitor of constitutively active rhodopsin mutants found in patients with autosomal dominant retinitis pigmentosa

Cited by 15 publications

References 34 publications

Constitutively Active Rhodopsin and Retinal Disease

Constitutively Active Rhodopsin and Retinal Disease

Pharmacological Chaperone-mediated in Vivo Folding and Stabilization of the P23H-opsin Mutant Associated with Autosomal Dominant Retinitis Pigmentosa

Aberrant Metabolites in Mouse Models of Congenital Blinding Diseases: Formation and Storage of Retinyl Esters

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