During the last funding period we combined transgenic mouse technology with electrophysiological, biochemical, and morphological analyses in a multidisciplinary approach to study rhodopsin deactivation in vivo. We obtained detailed information on mechanisms of rhodopsin deactivation. In addition, we observed the cellular consequence of defective rhodopsin shut off. In this proposal I will use a similar approach to (1) study cone opsin deactivation and (2) investigate pathogenic mechanisms of light-dependent photoreceptor cell death. Due to the paucity of cone cells in the retina of most experimental animal models, little is known about phototransduction mechanisms underlying the cone response. In the first aim I propose to use transgenic techniques to reconstitute the S-opsin deactivation components in rod cells of transgenic mice. In our studies, we will measure and compare rates of thermal isomerization, efficiency of transducin activation, time constant of MII decay and time constant of pigment regeneration between rhodopsin and S-opsin to see whether these parameters contribute to differences in behavior between rod and cone responses. We will also test the hypothesis that multiple phosphorylations of S-opsin, followed by cone arrestin binding, are steps necessary for its rapid and timely deactivation. I anticipate that a detailed and systematic comparison between rod and cone deactivation pathways in an environment that approximates the native state will provide a good start to understanding phototransduction mechanism in cones. In the second aim, I propose to study the mechanisms underlying light-induced photoreceptor cell death. First, I will test the hypothesis that accumulation of rhodopsin/arrestin complex, a pathogenic mechanism in Drosophila, is conserved in vertebrates. Second, I propose to use a combination of expression arrays and proteomics analyses to compare and contrast expression changes in different mouse models of light damage due to constitutive signaling

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-SSS-P (06))
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Mariani, Andrew P
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University of Southern California
Anatomy/Cell Biology
Schools of Medicine
Los Angeles
United States
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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; Peshenko, Igor V; Chen, Jeannie et al. (2018) Guanylate cyclase-activating protein 2 contributes to phototransduction and light adaptation in mouse cone photoreceptors. J Biol Chem 293:7457-7465
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
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:
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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