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

Proc Natl Acad Sci U S A. 2014 Apr 1;111(13):5024-9. doi: 10.1073/pnas.1400780111. Epub 2014 Mar 20.


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.

Keywords: ABC transporters; Stargardt disease; photoreceptor degeneration; retinal pigment epithelial cells; retinoids.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / metabolism*
  • Adenosine Triphosphate / metabolism
  • Animals
  • Biological Transport / drug effects
  • Cattle
  • Cytoprotection / drug effects*
  • Isomerism
  • Mice
  • Models, Biological
  • Phosphatidylcholines / metabolism
  • Phosphatidylethanolamines / chemistry
  • Phosphatidylethanolamines / metabolism
  • Photoreceptor Cells, Vertebrate / cytology*
  • Photoreceptor Cells, Vertebrate / drug effects
  • Photoreceptor Cells, Vertebrate / metabolism*
  • Proteolipids / metabolism
  • Retinoids / chemistry
  • Retinoids / metabolism
  • Rod Cell Outer Segment / drug effects
  • Rod Cell Outer Segment / metabolism
  • Sus scrofa
  • Vitamin A / chemistry*
  • Vitamin A / toxicity*


  • 1,2-dioleoyl-glycero-3-phosphatidyl ethanolamine
  • ATP-Binding Cassette Transporters
  • N-retinylidene-phosphatidylethanolamine
  • Phosphatidylcholines
  • Phosphatidylethanolamines
  • Proteolipids
  • Retinoids
  • proteoliposomes
  • Vitamin A
  • Adenosine Triphosphate
  • 1,2-oleoylphosphatidylcholine