The absorption of photons in rods and cones of the retina activates a cascade of biochemical reactions (phototransduction cascade) that generates the electrical response to light. The activation and deactivation of the cascade ultimately limits the amplitude and kinetics of the transduced signal, and thus the sensitivity and temporal resolution of vision. The overall goal of this study is to understand the mechanisms that turn off the light response in intact mouse photoreceptors. Gene targeting techniques will be used to manipulate the function of a subset of proteins that have been suggested to play key roles in deactivation of the cascade, and the resulting changes in the photoresponses of single rod cells will be determined by electrical recording and changes in protein localization determined by real-time 2-photon imaging. Using these approaches, we will address three important questions: (1) What is the time course of rhodopsin deactivation, and how is it determined by the interactions between rhodopsin kinase (GRK1) and arrestin (Arr1)? (2) How does G*-E* deactivation determine recovery of the flash response, and how does changing the rate of this deactivation get relayed across the synapse to affect visual function? and (3) What are the long-lasting mechanisms of light adaptation that alter the kinetics of photoresponse deactivation?

Public Health Relevance

Relevance This research will provide a fundamental mechanistic understanding of the initial steps in the normal visual process and adaptation, which may help to provide insights for the pathogenesis of diseases that arise from failures of deactivation, such as in some forms of retinitis pigmentosa, Oguchi disease, Nougaret's nightblindness, and rod-cone dystrophy. This research addresses one of the objectives recommended by the Retinal Diseases Panel (http://www.nei.nih.gov/strategicplanning/np_retinal.asp#obj), which is to Analyze the mechanisms underlying light adaptation and recovery following phototransduction and understand the changes in neural coding in light/dark adaptation. In a broader context, these experiments will provide reveal new knowledge of deactivation of G-protein cascades in general, which all eukaryotic cells use to transduce extracellular signals into intracellular responses.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY014047-12
Application #
8449201
Study Section
Special Emphasis Panel (ZRG1-CB-G (90))
Program Officer
Neuhold, Lisa
Project Start
2002-05-01
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
12
Fiscal Year
2013
Total Cost
$487,932
Indirect Cost
$168,709
Name
University of California Davis
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Burns, Marie E; Levine, Emily S; Miller, Eric B et al. (2016) New Developments in Murine Imaging for Assessing Photoreceptor Degeneration In Vivo. Adv Exp Med Biol 854:269-75
Zhang, Pengfei; Goswami, Mayank; Zam, Azhar et al. (2015) Effect of scanning beam size on the lateral resolution of mouse retinal imaging with SLO. Opt Lett 40:5830-3
Fortenbach, Christopher R; Kessler, Christopher; Peinado Allina, Gabriel et al. (2015) Speeding rod recovery improves temporal resolution in the retina. Vision Res 110:57-67
Kessler, Christopher; Tillman, Megan; Burns, Marie E et al. (2014) Rhodopsin in the rod surface membrane regenerates more rapidly than bulk rhodopsin in the disc membranes in vivo. J Physiol 592:2785-97
Arshavsky, Vadim Y; Burns, Marie E (2014) Current understanding of signal amplification in phototransduction. Cell Logist 4:e29390
Levine, Emily S; Zam, Azhar; Zhang, Pengfei et al. (2014) Rapid light-induced activation of retinal microglia in mice lacking Arrestin-1. Vision Res 102:71-9
Long, James H; Arshavsky, Vadim Y; Burns, Marie E (2013) Absence of synaptic regulation by phosducin in retinal slices. PLoS One 8:e83970
Gross, Owen P; Pugh Jr, Edward N; Burns, Marie E (2012) Spatiotemporal cGMP dynamics in living mouse rods. Biophys J 102:1775-84
Arshavsky, Vadim Y; Burns, Marie E (2012) Photoreceptor signaling: supporting vision across a wide range of light intensities. J Biol Chem 287:1620-6
Gross, Owen P; Pugh Jr, Edward N; Burns, Marie E (2012) Calcium feedback to cGMP synthesis strongly attenuates single-photon responses driven by long rhodopsin lifetimes. Neuron 76:370-82

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