Precise regulation of cyclic GMP (cGMP) levels is required for the initial events of vision in the photoreceptor cells of the retina. Disruptions in the cGMP metabolic pathway, whether resulting from genetic mutations or from therapeutic drug treatments, can cause impaired vision and/or retinal disease (e.g., retinitis pigmentosa, congenital stationary night-blindness) in humans and in animals. While major advances have been made in understanding the molecular basis of visual transduction in rod photoreceptors, there remain important unanswered questions about how the central enzyme of visual excitation, cGMP phosphodiesterase (PDE6), is activated and regulated. Furthermore, two photoreceptor proteins, the glutamic acid-rich protein-2 (GARP2) and the 17 kDa prenyl binding protein (PrBP/d), interact with PDE6 but their functions during phototransduction remain unknown.
The specific aims of the research are to: 1. Determine how allosteric regulation of PDE6 by cGMP binding and by its inhibitory Pgamma subunit influence the magnitude and lifetime of transducin activation of PDE6. 2. Test the hypothesis that the glutamic acid-rich protein-2 (GARP2) regulates the catalytic activity of PDE6 in rod photoreceptors. 3. Define the role of the 17 kDa prenyl binding protein (PrBP/d) in the transport and regulation of PDE6 and other prenylated proteins in photoreceptor cells. Mutations in PDE6 subunits, as well as in proteins known to interact with GARP2 or PrBP/d, can cause retinal disease. With the increasing use of phosphodiesterase inhibitors to treat human diseases, the susceptibility of PDE6 to inhibition by these drugs is a concern. Understanding PDE6 regulation at the molecular level is critical for designing effective therapies for certain forms of retinal degeneration, and to better avoid adverse side effects from the use of phosphodiesterase inhibitors as therapeutic drugs. The central enzyme in the visual pathway of rods and cones is the photoreceptor phosphodiesterase (PDE6). Genetic mutations in this protein can lead to loss of visual function, retinal disease, and/or total blindness. With the recent upsurge in the use of phosphodiesterase inhibitors as treatments for a variety of human diseases, adverse effects on vision due to PDE6 inhibition must be considered. Understanding PDE6 at the molecular level is crucial for future efforts to cure certain forms of retinal disease, as well as in avoiding harmful side effects of therapeutic drugs targeting phosphodiesterases for other human diseases.
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