Retinal rods and cones utilize visual pigments that are coupled to G-protein signaling cascades to detect the presence of photons. Little is known about how these two cell types use such a remarkably similar phototransduction cascade to achieve their distinct functional properties. A major objective of this project is to address this fundamental question. An understanding of the mechanisms that regulate phototransduction also has important disease relevance because deregulated signaling that occurs at different transduction steps often has a negative impact on photoreceptor cell survival. Our second objective is to apply what we learned in phototransduction and translate that knowledge into a better understanding of disease mechanisms in rods and cones so that a rational therapeutic strategy can be devised. In the first aim, we will test the hypothesis that differences in the functional properties between rods and cones can be explained, in part, by the transduction efficiency between the visual pigment and transducin, the visual G-protein. This hypothesis is supported by our preliminary results that show a 100-fold decrease in sensitivity when cone transducin was placed downstream of rhodopsin. Experiments in Aim 1 will systematically analyze the contribution of the rod and cone isoforms of the heterotrimeric transducin subunits toward the observed decrease in transduction efficiency at this step. The potential function of the G?? subunit in controlling photoreceptor noise and response recovery will also be investigated. In the second aim, we will investigate the cell death pathways that are triggered by light exposure or genetic mutations that lead to """"""""equivalent light"""""""". Experiments in Aim 2 are designed (a) to probe the underlying mechanism for the toxicity of the rhodopsin/arrestin complex;(b) to investigate whether endocytosis of the rhodopsin/arrestin complex is required to generate the cell death signal;(c) to analyze whether constitutive phototransduction in cones is a potential mechanism for cell death;and (d) to study the involvement of ATF-3 and ATF-4 transcriptional regulators in the cellular response to light damage. The outcome from these experiments will address the fundamental question as to how cells may utilize G-protein signaling cascades, which consist of highly similar protein members, to achieve diverse signaling properties. In addition, we will gain a better understanding of the relationship between defective signaling and disease.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY012155-13
Application #
7768393
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Mariani, Andrew P
Project Start
1998-03-01
Project End
2012-02-29
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
13
Fiscal Year
2010
Total Cost
$588,040
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
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LaVail, Matthew M; Nishikawa, Shimpei; Steinberg, Roy H et al. (2018) Phenotypic characterization of P23H and S334ter rhodopsin transgenic rat models of inherited retinal degeneration. Exp Eye Res 167:56-90
Vinberg, Frans; Chen, Jeannie; Kefalov, Vladimir J (2018) Regulation of calcium homeostasis in the outer segments of rod and cone photoreceptors. Prog Retin Eye Res 67:87-101
Wang, Tian; Reingruber, J├╝rgen; Woodruff, Michael L et al. (2018) The PDE6 mutation in the rd10 retinal degeneration mouse model causes protein mislocalization and instability and promotes cell death through increased ion influx. J Biol Chem 293:15332-15346
Vinberg, Frans; Wang, Tian; De Maria, Alicia et al. (2017) The Na+/Ca2+, K+ exchanger NCKX4 is required for efficient cone-mediated vision. Elife 6:
Wang, Tian; Tsang, Stephen H; Chen, Jeannie (2017) Two pathways of rod photoreceptor cell death induced by elevated cGMP. Hum Mol Genet 26:2299-2306
Rose, Kasey; Walston, Steven T; Chen, Jeannie (2017) Separation of photoreceptor cell compartments in mouse retina for protein analysis. Mol Neurodegener 12:28
Lee, Amy S; Brandhorst, Sebastian; Rangel, Daisy F et al. (2017) Effects of Prolonged GRP78 Haploinsufficiency on Organ Homeostasis, Behavior, Cancer and Chemotoxic Resistance in Aged Mice. Sci Rep 7:40919
Cho, Jung-Hwa; Swanson, Carter J; Chen, Jeannie et al. (2017) The GCaMP-R Family of Genetically Encoded Ratiometric Calcium Indicators. ACS Chem Biol 12:1066-1074
Sakurai, Keisuke; Vinberg, Frans; Wang, Tian et al. (2016) The Na(+)/Ca(2+), K(+) exchanger 2 modulates mammalian cone phototransduction. Sci Rep 6:32521

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