The overall goal of this proposal is to define new molecular and cellular mechanisms that enable vertebrate photoreceptors to adapt to constantly changing conditions of ambient illumination. We will focus on the massive light-driven translocation of major signaling proteins between the subcellular compartments of the photoreceptor cell, a phenomenon which has attracted overwhelming interest throughout the visual community over the past few years. We will continue to explore the mechanistic aspects and the physiological role of protein translocation and will extend our efforts to address the potential involvement of protein translocation in photoreceptor neuroprotection. The first two Aims are devoted to the translocation of arrestin. Our recent findings indicate that arrestin translocation is triggered at a critical threshold of light intensity by a specific signaling mechanism. The nature of this mechanism will be elucidated in Aim 1. The fact that arrestin is a key player in inactivation of the visual signaling cascade suggests that its light-driven translocation to the light- sensitive compartment of the photoreceptor cell, the outer segment, contributes to light adaptation by making light responses less sensitive and more rapid. This hypothesis will be directly addressed in Aim 2. The other two Aims are focused on the translocation of transducin.
In Aim 3 we will follow up on our recent finding that a protein called phosducin serves as a trafficking chaperone for transducin translocation. We will test the hypothesis that the light-dark cycle of transducin translocation is regulated through the concurrent cycle of phosducin phosphorylation and dephosphorylation. Finally, in Aim 4, we will use the mechanistic information learned during the previous grant cycle to generate a mouse model in which transducin translocation is impaired but other transducin functions are preserved. We will utilize this model to explore the putative role of transducin translocation in the neuroprotection of the rod from metabolic and oxidative stress imposed on rods during the many decades of their regular exposure to light. The proposed experiments are relevant to understanding the molecular and cellular mechanisms that regulate normal photoreceptor activity, mechanisms that may be perturbed in several degenerative retinal diseases, both inherited and associated with aging. The studies proposed in this application address the molecular and cellular mechanisms that allow our visual system to efficiently adapt to the drastic variations in light intensity encountered during a normal day. We will explore the role of these mechanisms in the neuroprotection of the photoreceptor cells from the metabolic and oxidative stresses they experience during the lifetime of light exposure. Because these mechanisms are likely to be perturbed in a variety of degenerative diseases of the retina, both inherited and associated with aging, addressing these questions on a molecular level opens doors for developing strategies for disease prevention and future therapeutic interventions.
|Pearring, Jillian N; Salinas, Raquel Y; Baker, Sheila A et al. (2013) Protein sorting, targeting and trafficking in photoreceptor cells. Prog Retin Eye Res 36:24-51|
|Lobanova, Ekaterina S; Finkelstein, Stella; Skiba, Nikolai P et al. (2013) Proteasome overload is a common stress factor in multiple forms of inherited retinal degeneration. Proc Natl Acad Sci U S A 110:9986-91|
|Arshavsky, Vadim Y; Burns, Marie E (2012) Photoreceptor signaling: supporting vision across a wide range of light intensities. J Biol Chem 287:1620-6|
|Rebrik, Tatiana I; Botchkina, Inna; Arshavsky, Vadim Y et al. (2012) CNG-modulin: a novel Ca-dependent modulator of ligand sensitivity in cone photoreceptor cGMP-gated ion channels. J Neurosci 32:3142-53|
|Herrmann, Rolf; Heflin, Stephanie J; Hammond, Timothy et al. (2011) Rod vision is controlled by dopamine-dependent sensitization of rod bipolar cells by GABA. Neuron 72:101-10|
|Reidel, Boris; Thompson, J Will; Farsiu, Sina et al. (2011) Proteomic profiling of a layered tissue reveals unique glycolytic specializations of photoreceptor cells. Mol Cell Proteomics 10:M110.002469|
|Osawa, Shoji; Jo, Rebecca; Xiong, Yubin et al. (2011) Phosphorylation of G protein-coupled receptor kinase 1 (GRK1) is regulated by light but independent of phototransduction in rod photoreceptors. J Biol Chem 286:20923-9|
|Herrmann, Rolf; Lobanova, Ekaterina S; Hammond, Timothy et al. (2010) Phosducin regulates transmission at the photoreceptor-to-ON-bipolar cell synapse. J Neurosci 30:3239-53|
|Lobanova, Ekaterina S; Herrmann, Rolf; Finkelstein, Stella et al. (2010) Mechanistic basis for the failure of cone transducin to translocate: why cones are never blinded by light. J Neurosci 30:6815-24|
|Rajala, Ammaji; Daly, Roger J; Tanito, Masaki et al. (2009) Growth factor receptor-bound protein 14 undergoes light-dependent intracellular translocation in rod photoreceptors: functional role in retinal insulin receptor activation. Biochemistry 48:5563-72|
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