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An S-opsin knock-in mouse (F81Y) reveals a role for the native ligand 11-cis-retinal in cone opsin biosynthesis.

http://www.ncbi.nlm.nih.gov/pubmed/22674284

In absence of their natural ligand, 11-cis-retinal, cone opsin G-protein-coupled receptors fail to traffic normally, a condition associated with photoreceptor degeneration and blindness. We created a mouse with a point mutation (F81Y) in cone S-opsin. As expected, cones with this knock-in mutation respond to light with maximal sensitivity red-shifted from 360 to 420 nm, consistent with an altered interaction between the apoprotein and ligand, 11-cis-retinal. However, cones expressing F81Y S-opsin showed an ∼3-fold reduced absolute sensitivity that was associated with a corresponding reduction in S-opsin protein expression. The reduced S-opsin expression did not arise from decreased S-opsin mRNA or cone degeneration, but rather from enhanced endoplasmic reticulum (ER)-associated degradation of the nascent protein. Exogenously increased 11-cis-retinal restored F81Y S-opsin protein expression to normal levels, suggesting that ligand binding in the ER facilitates proper folding. Immunohistochemistry and electron microscopy of normal retinas showed that Mueller cells, which synthesize a precursor of 11-cis-retinal, are closely adjoined to the cone ER, so they could deliver the ligand to the site of opsin synthesis. Together, these results suggest that the binding of 11-cis-retinal in the ER is important for normal folding during cone opsin biosynthesis.

Pubmed ID: 22674284 RIS Download

Mesh terms: Algorithms | Animals | Animals, Genetically Modified | Blotting, Western | Electrophysiological Phenomena | Endoplasmic Reticulum | Fluorescent Antibody Technique | Immunohistochemistry | Immunoprecipitation | Light | Mice | Mice, Inbred C57BL | Mice, Knockout | Microscopy, Electron | Mutation | Opsins | Real-Time Polymerase Chain Reaction | Receptors, G-Protein-Coupled | Retinal Cone Photoreceptor Cells | Retinal Rod Photoreceptor Cells | Retinaldehyde

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Associated grants

  • Agency: NEI NIH HHS, Id: EY02660
  • Agency: NEI NIH HHS, Id: R01 EY002660

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