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?
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.
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