Trafficking of membrane-associated proteins to cone photoreceptor outer segments requires the chromophore 11-cis-retinal.
Lecithin retinol acyl transferase (LRAT) and retinal pigment epithelium protein 65 (RPE65) are key enzymes of the retinoid cycle. In Lrat(-/-) and Rpe65(-/-) mice, models of human Leber congenital amaurosis, the retinoid cycle is disrupted and 11-cis-retinal, the chromophore of visual pigments, is not produced. The Lrat(-/-) and Rpe65(-/-) retina phenotype presents with rapid sectorial cone degeneration, and the visual pigments, S-opsin and M/L-opsin, fail to traffic to cone outer segments appropriately. In contrast, rod opsin traffics normally in mutant rods. Concomitantly, guanylate cyclase 1, cone T alpha-subunit, cone phosphodiesterase 6alpha' (PDE6alpha'), and GRK1 (G-protein-coupled receptor kinase 1; opsin kinase) are not transported to Lrat(-/-) and Rpe65(-/-) cone outer segments. Aberrant localization of these membrane-associated proteins was evident at postnatal day 15, before the onset of ventral and central cone degeneration. Protein levels of cone T alpha and cone PDE6alpha' were reduced, whereas their transcript levels were unchanged, suggesting posttranslational degradation. In an Rpe65(-/-)Rho(-/-) double knock-out model, trafficking of cone pigments and membrane-associated cone phototransduction polypeptides to the outer segments proceeded normally after 11-cis-retinal administration. These results suggest that ventral and central cone opsins must be regenerated with 11-cis-retinal to permit transport to the outer segments. Furthermore, the presence of 11-cis-retinal is essential for proper transport of several membrane-associated cone phototransduction polypeptides in these cones.
Zhang
Houbin
H
Department of Ophthalmology, University of Utah Health Science Center, Salt Lake City, Utah 84132, USA.
Fan
Jie
J
Li
Sha
S
Karan
Sukanya
S
Rohrer
Baerbel
B
Palczewski
Krzysztof
K
Frederick
Jeanne M
JM
Crouch
Rosalie K
RK
Baehr
Wolfgang
W
D000217:Acyltransferases / Q000172:deficiency / Q000378:metabolism; D000818:Animals; D001766:Blindness / Q000151:congenital / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000209:etiology / Q000503:physiopathology; D020033:Protein Isoforms / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000378:metabolism; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism* / Q000503:physiopathology; D012168:Retinal Pigments / Q000378:metabolism; D012172:Retinaldehyde / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D017299:Rod Opsins / Q000378:metabolism; D013997:Time Factors; D014785:Vision, Ocular; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
D000217:Acyltransferases; D002352:Carrier Proteins; D005136:Eye Proteins; D006162:Guanylate Cyclase; D008565:Membrane Proteins; D020033:Protein Isoforms; D011956:Receptors, Cell Surface; D012168:Retinal Pigments; D012172:Retinaldehyde; D017299:Rod Opsins; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase; C508769:R9AP protein, mouse; C110715:guanylate cyclase 1; C056942:lecithin-retinol acyltransferase