G protein signaling pathways in the retina are critically involved in reception and transduction of visual stimuli. The physiological operation of these pathways is dependent on the tight control of signal duration mediated by the Regulators of G protein signaling (RGS) proteins. Our long term goal is to elucidate the functional role of RGS protein in the retina signaling as a necessary prerequisite to understanding visual dysfunctions and therapeutic means of their treatment. The main focus of this proposal is on the R7 family of RGS proteins that are expressed in the retina where they control the rate of G protein inactivation during visual signal transmission. Research over the past several years have established the functional role of one R7 RGS member, RGS9, which utilizes a complex network of macromolecular interactions to shape the response of photoreceptors to light. The central HYPOTHESIS of this study is that the functional principles of RGS9 in photoreceptors also govern the function of other homologous R7 RGS proteins in retina neurons. We, therefore, suggest to utilize the wealth of methodological approaches and concepts developed in the studies of RGS9 in photoreceptors to gain insights into the organization and functional regulation of R7 RGS proteins through their macromolecular interactions. Specifically, our hypothesis will be addressed in the following SPECIFIC AIMS: 1. To elucidate the molecular mechanism of Gbeta5 action. We will perform detailed molecular and kinetic analysis to analyze how Gbeta5 regulates the activity of R7 RGS proteins. 2. To determine the functional significance of R7 RGS association with their membrane anchor, R7BP (R7 Binding Protein) using mouse models. Using mouse transgenic and knockout technology we will address the role of this newly discovered regulator of R7 RGS proteins in the retina. 3. To identify G proteins regulated by R7 RGS proteins in retina neurons. These studies should provide a better understanding of the regulation of signaling in the retina and generate insights into the molecular mechanisms of G protein signal disruption that lead to visual disorders and blindness.
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