To withstand the hazards of a lifetime's exposure to light, visual receptor cells have developed a strategy of maintenance which involves turnover of the photoreceptive membrane and its resident proteins. Understanding this recycling process, as well as how any defects in this process can lead to blindness, has been one of the primary missions of photoreceptor research over the last quarter century. While turnover has best been described at the level of removal and disposal of spent membrane, this proposal's focus is at the level of renewal. Specifically, the regulation of synthesis of opsin [the paramount protein of photoreceptive organelles] and of its export to the photoreceptive membranes will come under close scrutiny. Through vitamin A deprivation and replacement experiments, it has been recently established that this molecule, the chromophore of the opsin protein, has important trophic effects in regulating the health of the visual receptors. This work has been accomplished in the fruit fly Drosophila as well as in the rat, and important differences exist for a comparative study of the cell biology of intracellular routing of this critical visual protein. A program of research centered around the advantages of Drosophila for molecular analyses will address the question of how vitamin A exerts its influence over opsin synthesis. An exciting and likely possibility here is that vitamin A acts through the opsin gene itself at the locus of the gene's promotor, and, if this hypothesis should prove true, this mechanism would represent a novel example of gene regulation. In the rat, deprivation of vitamin A does not alter the density of opsin protein in the visual membranes, but it decreases the functional pigment [rhodopsin] as well as the size of the organelle [the rod outer segment]. The mechanism of recovery in this mammalian model will be explored in detail and compared and contrasted with the situation in Drosophila. In addition to the importance of this line of research in understanding the causes and prevention of blindness, it has a benefit in understanding basic aspects of the cell biology of protein trafficking and regulation of synthesis.
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