G protein signaling pathways in the retina are critically involved in reception and transduction of visual stimuli. The physiological operation of these pathways depends on the tight control provided by the Regulators of G protein signaling (RGS) proteins. Our long term goal is to elucidate molecular and cellular mechanisms of RGS protein function in shaping retina signaling as a necessary prerequisite to understanding visual dysfunctions and therapeutic means of their treatment. At the first visual synapse, G protein cascade driven by mGluR6 receptor, mediates the responses of ON-bipolar cells to light induced changes in neurotransmitter glutamate release from the photoreceptors. The dysregulation of signal transmission in ON-bipolar pathway causes congenital stationary night blindness, a visual disease characterized by the loss of dim vision. The members of the R7 subfamily of RGS protein, RGS7 and RGS11, are specifically concentrated at the ON-bipolar cell synapses where they form physical complexes with their auxiliary subunits G 5, R7BP, and R9AP as well as with the principal receptor, mGluR6. Disruption of R7 RGS proteins or mGluR6 leads to synaptic deficits and abolishes the responses of ON-bipolar cells to light. These observations lead to the central hypothesis of the proposal that components of R7 RGS complexes play essential role in regulating mGluR6 pathway and mediating synapse homeostasis. This hypothesis will be tested by pursuing three complementary Specific Aims: (1) To establish a role of the RGS complexes in functional homeostasis of the first visual synapse, (2) To determine mechanisms underlying selective delivery of the RGS complexes to the ON-BC dendrites, and (3) To understand kinetic requirements of G protein inactivation in the mGluR6 cascade. The strategy proposed to address these aims will entail a synergistic combination of biochemical, molecular biological, electrophysiological, and physiological approaches, each exploiting the existence of a powerful array of reagents and animal models. Better understanding of the RGS protein function and mGluR6 pathway regulation will yield important insights into the general principles of G protein involvement in synaptic transmission events and may suggest novel nodes of intervention for therapeutic strategies designed to treat inherited types of night blindness.
Normal vision is hinged on the function of the intracellular G protein signaling pathways in retina neurons. Dysregulation of these pathways affects fundamental processes including cellular survival, light reception, and synaptic transmission, and is a leading cause of visual disorders and blindness. The work proposed herein will yield a clearer understanding of the molecules involved in the regulation of G protein pathways in the retina and thus will aid in the rational design of effective therapeutic interventions.
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