The Molecular Mechanism of Retinal Degeneration in the Retinal Degeneration B (rdgB) Mutant of Drosophila
The rdgB Drosophila is a retinal degeneration mutant that reveals its characteristic phenotype when the fly is exposed to light. It was therefore inferred that some intermediate step along the phototransduction pathway is inactivated by the normal rdgB gene product and when the latter is defective, an unbalanced action of this intermediate brings about retinal degeneration. Recent studies have indicated that in invertebrate photoreceptors, the inositol lipid signaling system mediates phototransduction. To localize the stage in the phototransduction cascade with which the rdgB gene product interacts, we applied to the rdgB eyes chemicals that can activate specific photoreceptor proteins in the dark. Application of F−, GTPγS and phorbol ester to eyes of rdgB flies led to a degeneration of the photoreceptors that was indistinguishable from that caused by light. Application of the above reagents to the eyes of wild type flies had no effect. We suggest that light or the above chemical reagents activate protein kinase C, via G-protein -activated phospholipase C, resulting in an excessive phosphorylation of proteins in rdgB eyes relative to wild type flies. This suggestion was supported by pulse labeling with 32P-phosphate which showed a much greater incorporation of 32P-labeled proteins in rdgB relative to wild type eyes. The abnormal appearance of regenerative Ca2+ spikes in the terminals of the degenerating rdgB photoreceptors suggests that imbalanced regulation of voltage- and phosphorylation-dependent Ca2+ channels by protein kinase and deficient phosphatase activities result in a toxic increase in intracellular Ca2+ that leads to degeneration. This suggested mechanism was supported by the inhibition of the light-induced retinal degeneration following application of diltiazem, a Ca2+ channel blocker, to rdgB flies raised in the light.
KeywordsPhorbol Ester Photoreceptor Cell Retinal Degeneration Fast Time Scale Photoreceptor Degeneration
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