RT Journal Article SR Electronic T1 An S-Opsin Knock-In Mouse (F81Y) Reveals a Role for the Native Ligand 11-cis-Retinal in Cone Opsin Biosynthesis JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 8094 OP 8104 DO 10.1523/JNEUROSCI.0131-12.2012 VO 32 IS 23 A1 Christine Insinna A1 Lauren L. Daniele A1 Jason A. Davis A1 DeLaine D. Larsen A1 Colleen Kuemmel A1 Jinhua Wang A1 Sergei S. Nikonov A1 Barry E. Knox A1 Edward N. Pugh, Jr. YR 2012 UL http://www.jneurosci.org/content/32/23/8094.abstract AB 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.