Both rod and cone photoreceptors absorb light, triggering an amplification cascade, which produces membrane hyperpolarization through closure of selective ion channels. Radiating from the light-initiated event is a G-protein-coupled response of secondary activities, including rhodopsin or cone opsin receptor shut-off through a GRK1 phosphorylation and subsequent binding of either rod or cone arrestin. Cone photoreceptors are distinct from rods in morphology, light sensitivity, recovery rate, thermal stability, timing of outer segment shedding and resistance to programmed cell death by apoptosis. Characterization of the dynamic interactions and functions of these cone gene and their gene products may provide a basis for diagnosis, treatment or prevention of age related macular degeneration and other retinal rod and cone degenerations, thus preserving vision for currently untreatable forms of blindness. To address the distinct aspects inherent to the cone photo-transduction pathway and to accomplish our goals, experiments are designed to explore the function(s) of cone arrestin (CAR), its targeted G protein-coupled receptors (S and M opsin pigments) and other potential relevant partners in the cone synapse. Our working hypothesis, based in part on our ongoing biochemical and electrophysiological studies, support a role for CAR in regulating cone photo-transduction through binding to light-activated, GRK1 phosphorylated S and M opsins. We propose that when this X-chromosomal gene encoding CAR is genetically deleted with mouse knockout (KO) technology, a defective receptor shut-off will lead to a delayed recovery of cone photoresponses. To test this hypothesis, the specific aims and experimental design include 1) characterization of the morphological, biochemical and electrophysiological retinal phenotypes of the newly generated Car KO. Further experiments will explore these parameters in Grk1/Car double KO mice on two genetic backgrounds (transducin alpha -/- with normal rod morphology but no rod response and Nrl -/- with pure cone retina) compared to wildtype; 2) examine the effects of Grk1 S and M opsin phosphorylation and CAR binding on the cone visual retinoid cycle pathway; and 3) identification of other potential interacting cone synaptic partners for CAR and its alternatively spliced isoforms. Studies of the photo-transduction cascade and the molecular triggers for initiation and termination of high acuity vision are vital for sustaining lifelong vision. ? ?

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY015851-02
Application #
7126808
Study Section
Special Emphasis Panel (ZRG1-CB-G (90))
Program Officer
Mariani, Andrew P
Project Start
2005-09-30
Project End
2010-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
2
Fiscal Year
2006
Total Cost
$358,132
Indirect Cost
Name
University of Southern California
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Kim, Hwa Sun; Huang, Shun-Ping; Lee, Eun-Jin et al. (2018) Identifying Key Networks Linked to Light-Independent Photoreceptor Degeneration in Visual Arrestin 1 Knockout Mice. Adv Exp Med Biol 1074:281-287
Eandi, Chiara M; Charles Messance, Hugo; Augustin, S├ębastien et al. (2016) Subretinal mononuclear phagocytes induce cone segment loss via IL-1?. Elife 5:
Deming, Janise D; Van Craenenbroeck, Kathleen; Eom, Yun Sung et al. (2016) Characterization of Antibodies to Identify Cellular Expression of Dopamine Receptor 4. Adv Exp Med Biol 854:663-70
Yu, Wan-Qing; Eom, Yun Sung; Shin, Jung-A et al. (2016) Reshaping the Cone-Mosaic in a Rat Model of Retinitis Pigmentosa: Modulatory Role of ZO-1 Expression in DL-Alpha-Aminoadipic Acid Reshaping. PLoS One 11:e0151668
Shin, Jung-A; Eom, Yun Sung; Yu, Wan-Qing et al. (2015) TIMP-1 affects the spatial distribution of dendritic processes of second-order neurons in a rat model of Retinitis Pigmentosa. Exp Eye Res 140:41-52
Deming, Janise D; Pak, Joseph S; Shin, Jung-A et al. (2015) Arrestin 1 and Cone Arrestin 4 Have Unique Roles in Visual Function in an All-Cone Mouse Retina. Invest Ophthalmol Vis Sci 56:7618-28
Deming, Janise D; Pak, Joseph S; Brown, Bruce M et al. (2015) Visual Cone Arrestin 4 Contributes to Visual Function and Cone Health. Invest Ophthalmol Vis Sci 56:5407-16
Berkowitz, Bruce A; Gorgis, Jawan; Patel, Ankit et al. (2015) Development of an MRI biomarker sensitive to tetrameric visual arrestin 1 and its reduction via light-evoked translocation in vivo. FASEB J 29:554-64
Berkowitz, Bruce A; Murphy, Geoffrey G; Craft, Cheryl Mae et al. (2015) Genetic dissection of horizontal cell inhibitory signaling in mice in complete darkness in vivo. Invest Ophthalmol Vis Sci 56:3132-9
Pak, Joseph S; Lee, Eun-Jin; Craft, Cheryl Mae (2015) The retinal phenotype of Grk1-/- is compromised by a Crb1 rd8 mutation. Mol Vis 21:1281-94

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