Deactivation mechanisms of rod phototransduction

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DESCRIPTION (provided by applicant): 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. Using this approach, we will address 3 important questions: (1) How rapidly does rhodopsin become phosphorylated, and what determines this time course? (2) What are the functional consequences of arrestin translocation on the photoresponse? (3) Are the photoreceptor-specific splice variants of the RGS9 complex uniquely suited for deactivating transducin/PDE, and how? and 4) What are the mechanisms that speed transducin/PDE deactivation during light adaptation? This research addresses 1 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." This research will help clarify the initial steps in the normal visual process, as well as the pathogenesis of diseases that arise from failures of deactivation, such as in some forms of retinitis pigmentosa and nightblindness. In a broader context, these experiments will provide insights into the mechanisms of deactivation of G protein cascades, which all eucaryotic cells use to transduce extracellular signals into intracellular responses.