Cone photoreceptors function under bright light conditions and are essential for color perception and vision with high temporal and spatial resolution. Remarkably, unlike rods, cones remain functional even in steady bright light and dark adapt rapidly. Both of these properties require rapid recycling of chromophore for regeneration of cone visual pigment. Biochemical studies and shortcomings of the canonical pigment epithelium pathway for chromophore recycling indicate the possible existence of a second, cone- specific chromophore pathway located in the retina and independent of the pigment epithelium. The function of such a pathway under physiological conditions, its role in photoreceptor physiology, and its regulation have not been investigated. We propose to use single-cell and whole retina recordings from mouse photoreceptors to characterize the physiological function of this novel visual cycle. Specifically, we will determine the ability of mammalian retina to promote pigment regeneration and dark adaptation in cones independently of the pigment epithelium. We will establish the role of the mammalian retina visual cycle in extending the dynamic range of cones during background adaptation and in accelerating the recovery of cone sensitivity during dark adaptation. We will determine whether the specificity of the mammalian retina visual cycle is based on the ability of cones, and not rods, to oxidize 11-cis retinol, recycled within the retina, into 11-cis retinal and use it for pigment regeneration. We will use available genetically modified mice and pharmacological tools to characterize key steps in the pathway and their modulation by chromophore-binding proteins expressed in the retina. Collectively, the experiments outlined in this proposal seek to establish the mechanisms that enable mammalian cones to function in rapidly varying light conditions, an essential property for the photoreceptors that mediate daytime vision. In addition to advancing the understanding of cone cell biology, our studies of the mammalian retina visual cycle have potential clinical implications. Mutations in the chromophore-binding proteins investigated in this study have been associated with multiple visual disorders including Stargardt disease, cone-rod dystrophy, and macular degeneration. No treatments currently exist for these disorders. Our experiments will lay the foundation for understanding how specific defects in the retina visual cycle produce cone-related retinal disorders, as well as for the development of new treatments targeting specifically the function of cones.

Public Health Relevance

The experiments outlined in this proposal seek to establish the mechanisms that enable mammalian cones to function in bright light, an essential property for the photoreceptors that mediate daytime vision. These studies will help us understand the mechanisms that regulate mammalian cone function under normal and pathological conditions.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY019312-05
Application #
8399104
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Neuhold, Lisa
Project Start
2008-12-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
5
Fiscal Year
2013
Total Cost
$343,094
Indirect Cost
$117,374
Name
Washington University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Sakurai, Keisuke; Vinberg, Frans; Wang, Tian et al. (2016) The Na(+)/Ca(2+), K(+) exchanger 2 modulates mammalian cone phototransduction. Sci Rep 6:32521
Ding, Xi-Qin; Thapa, Arjun; Ma, Hongwei et al. (2016) The B3 Subunit of the Cone Cyclic Nucleotide-gated Channel Regulates the Light Responses of Cones and Contributes to the Channel Structural Flexibility. J Biol Chem 291:8721-34
Sakurai, Keisuke; Chen, Jeannie; Khani, Shahrokh C et al. (2015) Regulation of mammalian cone phototransduction by recoverin and rhodopsin kinase. J Biol Chem 290:9239-50
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Vinberg, Frans; Kefalov, Vladimir (2015) Simultaneous ex vivo functional testing of two retinas by in vivo electroretinogram system. J Vis Exp :e52855
Zhang, Ning; Tsybovsky, Yaroslav; Kolesnikov, Alexander V et al. (2015) Protein misfolding and the pathogenesis of ABCA4-associated retinal degenerations. Hum Mol Genet 24:3220-37
Sarria, Ignacio; Pahlberg, Johan; Cao, Yan et al. (2015) Sensitivity and kinetics of signal transmission at the first visual synapse differentially impact visually-guided behavior. Elife 4:e06358
Berkowitz, Bruce A; Kern, Timothy S; Bissig, David et al. (2015) Systemic Retinaldehyde Treatment Corrects Retinal Oxidative Stress, Rod Dysfunction, and Impaired Visual Performance in Diabetic Mice. Invest Ophthalmol Vis Sci 56:6294-303

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