ATP-binding cassette transporter ABCA4 and chemical isomerization protect photoreceptor cells from the toxic accumulation of excess 11-cis-retinal.
The visual cycle is a series of enzyme-catalyzed reactions which converts all-trans-retinal to 11-cis-retinal for the regeneration of visual pigments in rod and cone photoreceptor cells. Although essential for vision, 11-cis-retinal like all-trans-retinal is highly toxic due to its highly reactive aldehyde group and has to be detoxified by either reduction to retinol or sequestration within retinal-binding proteins. Previous studies have focused on the role of the ATP-binding cassette transporter ABCA4 associated with Stargardt macular degeneration and retinol dehydrogenases (RDH) in the clearance of all-trans-retinal from photoreceptors following photoexcitation. How rod and cone cells prevent the accumulation of 11-cis-retinal in photoreceptor disk membranes in excess of what is required for visual pigment regeneration is not known. Here we show that ABCA4 can transport N-11-cis-retinylidene-phosphatidylethanolamine (PE), the Schiff-base conjugate of 11-cis-retinal and PE, from the lumen to the cytoplasmic leaflet of disk membranes. This transport function together with chemical isomerization to its all-trans isomer and reduction to all-trans-retinol by RDH can prevent the accumulation of excess 11-cis-retinal and its Schiff-base conjugate and the formation of toxic bisretinoid compounds as found in ABCA4-deficient mice and individuals with Stargardt macular degeneration. This segment of the visual cycle in which excess 11-cis-retinal is converted to all-trans-retinol provides a rationale for the unusually high content of PE and its long-chain unsaturated docosahexaenoyl group in photoreceptor membranes and adds insight into the molecular mechanisms responsible for Stargardt macular degeneration.
Department of Biochemistry and Molecular Biology, Centre for Macular Research, University of British Columbia, Vancouver, BC, Canada V6T 1Z3.
Faraz
F
Quazi
Robert S
RS
Molday
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002417:Cattle; D019610:Cytoprotection / Q000187:drug effects*; D007536:Isomerism; D051379:Mice; D008954:Models, Biological; D010713:Phosphatidylcholines / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000737:chemistry / Q000378:metabolism; D020419:Photoreceptor Cells, Vertebrate / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D011510:Proteolipids / Q000378:metabolism; D012176:Retinoids / Q000737:chemistry / Q000378:metabolism; D012374:Rod Cell Outer Segment / Q000187:drug effects / Q000378:metabolism; D034421:Sus scrofa; D014801:Vitamin A / Q000737:chemistry* / Q000633:toxicity*
C410262:1,2-dioleoyl-glycero-3-phosphatidyl ethanolamine; D018528:ATP-Binding Cassette Transporters; C497343:N-retinylidene-phosphatidylethanolamine; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D011510:Proteolipids; D012176:Retinoids; C020485:proteoliposomes; D014801:Vitamin A; D000255:Adenosine Triphosphate; C017251:1,2-oleoylphosphatidylcholine
ABC transporters; Stargardt disease; photoreceptor degeneration; retinal pigment epithelial cells; retinoids