Recovery of Phototransduction

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DESCRIPTION (provided by applicant): Our long-term objective is to apply the knowledge of phototransduction to understand general signaling mechanisms of heterotrimeric G-proteins. During the previous funding period we successfully identified transducin deactivation as the normal rate-limiting step of rod's recovery. We will test the generality of this finding in two other retinal G-proptein mediated pathways, namely, cone phototransduction and the mGluR6 pathway of the ON-type bipolar cells. The significance of understanding how visual signal is processed in these three cell types lies in the fact that they are adversely affected in many inherited retinal diseases. We will use gain-of-function and loss-of-function genetic manipulations in mice followed by biochemical, histological, and electrophysiological characterizations to test the following hypotheses: 1) rhodopsin deactivation is the second slowest step in rods' recovery; 2) the deactivation of cone transducin, rather than cone pigments, rate-limits normal cone recovery and 3) Gbeta5/RGS7 and Gbeta5/RGS11 protein complex are functionally redundant at the tips of the ON-type bipolar cell dendrites as the GAP for Galphao in the mGluR6 pathway. The three aims are in accordance with one of the program objectives set forth by NEI Retina Diseases Panel and have the potential to shed light into rod/cone differences and the roles of R7 RGS proteins and heterotrimeric G-proteins in the retina. This proposal examines the molecular and cellular mechanisms of visual signal transduction in retinas of genetically modified mice. The three cell types to be studied: rods, cones, and bipolar cells, are frequently affected in a variety of inherited retinal diseases.