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 photo responses of single rod cells will be determined by electrical recording. Using this approach, we will ask: (1) What are the mechanisms that produce the timely and reproducible deactivation of rhodopsin? (2) What protein interactions facilitate transducin and PDE deactivation in intact cells, and does this deactivation normally rate-limit response recovery? and (3) What deactivation step(s) are speeded during light 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 Oguchi disease. More generally, these experiments will provide insights into the mechanisms of deactivation of G protein cascades, which all cell types use to transduce extracellular signals into intracellular responses.