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

Christine Insinna, Lauren L. Daniele, Jason A. Davis, DeLaine D. Larsen, Colleen Kuemmel, Jinhua Wang, Sergei S. Nikonov, Barry E. Knox, Edward N Pugh Jr

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)8094-8104
Number of pages11
JournalJournal of Neuroscience
Volume32
Issue number23
DOIs
StatePublished - Jun 6 2012

ASJC Scopus subject areas

  • Neuroscience(all)

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    Insinna, C., Daniele, L. L., Davis, J. A., Larsen, D. D., Kuemmel, C., Wang, J., Nikonov, S. S., Knox, B. E., & Pugh Jr, E. N. (2012). An S-opsin knock-in mouse (F81Y) reveals a role for the native ligand 11-cis-retinal in cone opsin biosynthesis. Journal of Neuroscience, 32(23), 8094-8104. https://doi.org/10.1523/JNEUROSCI.0131-12.2012