G-proteins and mechanisms of signal transduction in vision

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DESCRIPTION (provided by applicant): Phototransduction in retinal rod photoreceptor cells relies on the prototypical mechanism of high-yield signal amplification mediated by the heterotrimeric G-protein transducin. A single light activated rhodopsin molecule activates several hundred transducin molecules, which relay the information about incoming visual signal from rhodopsin to the enzyme of the second messenger system, cGMP-phosphodiesterase. All aspects of transducin alpha subunit functions, especially its primary interactions with rhodopsin and rhodopsin catalyzed nucleotide exchange, require the transducin beta-gamma subunit complex. Discovered more than two decades ago, transducin beta-gamma has been studied by in-vitro experiments almost exclusively. The true in-vivo role of this protein complex during normal functioning or its involvement in retina diseases remains unknown. We have developed a novel tool to study the mechanisms of G-proteins in vision - a mouse model lacking the rod specific transducin gamma subunit. To characterize this model system, which we will make available to the broad vision research community, we propose to test major aspects of phototransduction, retina development and protein distribution. The key goal is to determine whether activation of visual signaling is possible at all without transducin beta-gamma complex, a problem that is not resolved by current in-vitro studies. In the future this model will also help to answer such important questions, as mechanisms of light adaptation, differences between rod and cone signaling, synaptic transmission, retina degeneration and others. G-protein beta-gamma complexes have recently emerged as new targets of drug design and therapeutic intervention. Thus, the functional characterization of this mouse model will be very valuable for understanding eye disease and potential new therapies in humans. PUBLIC HEALTH RELEVANCE: This project focuses on the first characterization of the mouse model system in which a key retinal protein, transducin beta-gamma complex, has been deleted. This model is being developed for use by the vision research community to help understand underlying mechanisms of retinal diseases in humans and facilitate novel therapeutic strategies.