The long-term objective of the proposed research is to understand in detail the cellular mechanisms underlying visual transduction in retinal rod and cone photoreceptors. The first specific aim is to understand more about light adaptation and the underlying Ca++ feedback in rods. In particular, we hope to examine: a) any change in the cGMP-gated channel's selectivity for Ca++ in background light, b) the relation between guanylate cyclase (the cGMP-synthesizing enzyme) and Ca++ under near-physiological conditions, c) any residual background light adaptation that is independent of the Ca++ feedback and d) any contribution of voltage-dependent conductances to the light adaptation shown by the voltage response of rods. The second specific aim is to understand more about the phototransduction mechanism and light adaptation in cones. In particular, we hope to find out: a) whether the dark metabolic flux for cGMP is faster than in rods, b) whether the modulation of the cone guanylate cyclase by Ca++ is quantitatively similar to that for the rod enzyme, and c) whether the various measurements made on cones can be integrated in a simple model to predict the cone's response behavior to light. The third specific aim is to characterize the retinal cGMP-activated channels at a molecular level. We hope to: a) make structure-function correlation studies of the rod channel through site-directed mutagenesis as well as construction of chimeric channels between the rod channel and a homologous channel in olfactory cilia, and b) molecularly clone the cGMP-gated channels in cones and possibly elsewhere in the retina. The electrophysiological experiments will be carried out on amphibian rods and cones as well as mammalian cones. The molecular biological studies, together with parallel electrical measurements, will be carried out on cGMP-activated channels derived from a human retinal cDNA library. A detailed knowledge of the phototransduction process is important for understanding various diseases affecting photoreceptors, such as retinitis pigmentosa.
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