RGS proteins are a family of regulators of G proteins, the mediators of signal transduction in retinal photoreceptor cells, and in most signal transduction pathways in mammals. One member of this family, RGS9-1, plays a key role as a regulator of photoresponse timing, and serves as a model for understanding the function of this large family. The goal of this project is to understand the role of RGS proteins, particularly those of the RGS9 subfamily, in regulating the timing and sensitivity of intracellular signaling cascades in the vertebrate retina. The focus will be on the roles of these proteins in the kinetics of recovery in rods and cones, on the molecular mechanisms through which these roles are played, and on determining the mechanisms by which accelerated recovery is achieved in cones, relative to recovery in rods. There are four specific aims: 1. To elucidate the molecular mechanisms of GTPase regulation in phototransduction, by combining structural and functional studies of purified GTPase accelerating proteins (RGS9-1 and related RGS proteins, Gbeta5L, and engineered forms and fragments of them) with physiological and biophysical studies of mice and frogs genetically altered to express these proteins. 2. To assess the role of GTPase acceleration relative to other recovery reactions in the fast recovery of cone photoresponses, and in the """"""""dominant time constant"""""""" of phototransduction, by quantifying the amounts of RGS9-1, Gbeta5L, and other phototransduction components in cones, and varying RGS9-1 and Gbeta5L levels in rods and cones. 3. To determine the mechanisms for modulation of RGS9-1 function by interactions with other photoreceptor proteins and lipids. 4. To determine the roles of RGS11 and RGS7 in vision by characterizing their multiple splice variants, identifying the retinal cells in which they are expressed, and identifying proteins with which they interact. Understanding the roles of RGS proteins in G protein signaling is necessary to understand how these pathways, which serve as targets for most drugs, normally function, how they are disrupted in disease states and how they are impacted by therapies. Understanding the role RGS of proteins in vision will help us understand normal vision, and provide insight into retinal diseases and potential therapies.
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