CGMP AND PHOTORECEPTOR FUNCTION

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Cyclic GMP (cGMP) is the primary intracellular messenger for visual transduction in retinal rod and cone photoreceptors. While the enzymatic components of the cGMP pathway have been identified and characterized, the regulatory mechanisms responsible for determining the cytosolic cGMP concentration during photoreceptor stimulation are not well understood. One unusual feature of rod outer segments is the presence of high concentrations of cGMP binding proteins which sequester most of the intracellular cGMP and lower the cytosolic levels of this second messenger. The functional significance of these cGMP binding sites is currently not understood. The overall hypothesis to be tested is that cGMP binding proteins control the cGMP concentration in rod photoreceptors by allosterically regulating the metabolism of cGMP in addition to acting as a cytoplasmic buffer to reduce the free cGMP concentration in the cytosol. The specific aims of the proposed research are: (1) To localize and identify the functional roles for high affinity and moderate affinity classes of cGMP binding sites which are present in rod outer segments; (2) To define the mechanisms, for the regulation of cGMP binding and metabolism that together control the free cytosolic concentration of cGMP during visual transduction in rod photoreceptor cells. Inherited defects in cGMP metabolism are known to result retinal degeneration and blindness. This study will provide insight into the normal mechanisms controlling cGMP metabolism and binding in rod photoreceptors so that new strategies may be developed to intervene with certain types of degenerative diseases of retinal photoreceptors.