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 transducin deactivation has been unequivocally identified as the normal rate-limiting step of rod's recovery. The generality of this finding will begin to be tested in two other retinal G-proptein mediated pathways, namely, cone phototransduction and the mGluR6 pathway of the ON-type bipolar cells. Gain-of-function and loss-of-function genetic manipulations of mouse genome, accompanied by biochemical, histological, and electrophysiological characterizations will be employed to test the following hypotheses in three specific aims: 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 dendritic tips of the ON-type bipolar cells. 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 on rod/cone differences and the roles of R7 RGS proteins and heterotrimeric G-proteins in the retina.
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