This project seeks to uncover the molecular mechanisms of RGS-mediated GTPase regulation in photoreceptor cells of the retina. The expression patterns for different RGS family members will be determined at the mRNA and protein levels, and correlated with patterns of G protein expression and cellular function. Much of the effort will be focused on RGS9, recently discovered to be a major phototransduction GAP, localized to rod and cone outer segments. Cloning and characterization of the mouse and human genes for RGS9 will facilitate determining the functional consequences of deficiencies of RGS9 in vivo and the biochemical bases for those effects will be determined. The relationships between structure and function of RGS9 will be systematically explored by comparisons within the RGS family by analysis of chimeric proteins, and by site-specific collaborative multidisciplinary efforts to explore the role of RGS9 in vision using techniques of molecular genetics, structural biophysics, electrophysiology, and enzymology. Regulation of RGS function by protein-protein interactions, calcium ions, and phosphorylation will also be explored. These studies will add an important piece currently missing from the phototransduction puzzle, and may provide important information on retinal disease resulting from defects in phototransduction components.
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