Cone photoreceptor cells initiate vision in daytime, operating in light intensities that saturate rods and render them useless to the visual system. The ability of cones to escape saturation relies in large part upon specializations of proteins, including cone opsins, within the cone phototransduction cascade that function in synergy to preserve inward cGMP-sensitive current in strong light. During their biosynthesis, cone opsins have a surprising need for the visual chromophore, 11-cis retinal, to achieve proper folding, and our preliminary data suggests that they also possess a compensating capacity for proteolytic degradation of misfolded proteins. The proposed work will lead to a comprehensive, molecularly based account of these specializations within cones, and could be used in future work to both extend the operating range of the much more numerous rods, and develop strategies that facilitate the generation of properly folded opsins or increase the capacity to degrade misfolded opsins.

Public Health Relevance

This research will provide novel, fundamental insights into the mechanisms of daytime vision, and into the mechanisms that govern the normal folding of the proteins that initiate daytime vision, the cone opsins, whose misfolding is implicated in cone- and cone-rod dystrophies. This research addresses two of the objectives recommended by the Retinal Diseases Panel (http://www.nei.nih.gov/strategicplanning/np_retinal.asp#obj) of the NEI, which are to Use both molecular and physiological approaches to study light adaptation in photoreceptors, with particular emphasis on the visual cycle ... and Understand the cell biology of cones, including outer segment renewal and shedding, the phototransduction cascade, retinoid metabolism, opsin trafficking, and the regulation of gene expression for cone pigments. (http://www.nei.nih.gov/strategicplanning/np_retinal.asp)

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY002660-35
Application #
8523859
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Neuhold, Lisa
Project Start
1978-08-01
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
35
Fiscal Year
2013
Total Cost
$499,721
Indirect Cost
$175,227
Name
University of California Davis
Department
Physiology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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Morgan, Jessica I W; Pugh Jr, Edward N (2013) Scanning laser ophthalmoscope measurement of local fundus reflectance and autofluorescence changes arising from rhodopsin bleaching and regeneration. Invest Ophthalmol Vis Sci 54:2048-59
Nikonov, Sergei S; Lyubarsky, Arkady; Fina, Marie E et al. (2013) Cones respond to light in the absence of transducin * subunit. J Neurosci 33:5182-94
Daniele, Lauren L; Insinna, Christine; Chance, Rebecca et al. (2011) A mouse M-opsin monochromat: retinal cone photoreceptors have increased M-opsin expression when S-opsin is knocked out. Vision Res 51:447-58
Calvert, Peter D; Schiesser, William E; Pugh Jr, Edward N (2010) Diffusion of a soluble protein, photoactivatable GFP, through a sensory cilium. J Gen Physiol 135:173-96
Naarendorp, Frank; Esdaille, Tricia M; Banden, Serenity M et al. (2010) Dark light, rod saturation, and the absolute and incremental sensitivity of mouse cone vision. J Neurosci 30:12495-507
Burns, Marie E; Pugh Jr, Edward N (2009) RGS9 concentration matters in rod phototransduction. Biophys J 97:1538-47
Daniele, Lauren L; Sauer, Brian; Gallagher, Shannon M et al. (2008) Altered visual function in monocarboxylate transporter 3 (Slc16a8) knockout mice. Am J Physiol Cell Physiol 295:C451-7
Nikonov, Sergei S; Brown, Bruce M; Davis, Jason A et al. (2008) Mouse cones require an arrestin for normal inactivation of phototransduction. Neuron 59:462-74
Feathers, Kecia L; Lyubarsky, Arkady L; Khan, Naheed W et al. (2008) Nrl-knockout mice deficient in Rpe65 fail to synthesize 11-cis retinal and cone outer segments. Invest Ophthalmol Vis Sci 49:1126-35

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