ATP-binding cassette transporter ABCA4 and chemical isomerization protect photoreceptor cells from the toxic accumulation of excess 11-cis-retinal

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-04, Vol.111 (13), p.5024-5029
• Main Authors: Quazi, Faraz, Molday, Robert S.
• Format: Article
• Language: English
• Subjects: Adenosine triphosphatase; Adenosine triphosphatases; Adenosine Triphosphate - metabolism; Animals; ATP binding cassette transporters; ATP-Binding Cassette Transporters - metabolism; Binding sites; Biological Sciences; Biological Transport - drug effects; Cattle; Cell cycle; Cytoprotection - drug effects; Isomerism; Isomerization; Isomers; Lipids; Liposomes; Macular degeneration; Membranes; Mice; Models, Biological; Phosphatidylcholines - metabolism; Phosphatidylethanolamines - chemistry; Phosphatidylethanolamines - metabolism; Photoreceptor Cells, Vertebrate - cytology; Photoreceptor Cells, Vertebrate - drug effects; Photoreceptor Cells, Vertebrate - metabolism; Photoreceptors; Proteolipids - metabolism; Retina; Retinal diseases; Retinal pigments; Retinoids; Retinoids - chemistry; Retinoids - metabolism; Rod Cell Outer Segment - drug effects; Rod Cell Outer Segment - metabolism; Sus scrofa; Vitamin A - chemistry; Vitamin A - toxicity
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1400780111

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.