Light detection is initiated by photoactivation of a G protein-coupled receptor, referred to as rhodopsin. This photopigment consists of a protein component known as the opsin, and a vitamin A derivative called the chromophore. The chromophore is the light-sensitive portion of the photopigment, which undergoes a cis-trans isomerization in response to light. In mammalian rods and cones the chromophore must be regenerated through an enzymatic pathway, referred to as the visual cycle. Defects in this cycle lead to a variety of degenerative diseases affecting the eye. In Drosophila and in human intrinsically photosensitive retinal ganglion cells (ipRGCs), the chromophore is thought to remain associated with the opsin following light stimulation, and the chromophore appears to be regenerated simply by exposure to a second photon of light. Thus, it was thought that these bistable photopigments do not rely on a visual cycle. Surprisingly, it was recently discovered that a similar visual cycle exists in flies. This opens the possibility of using flies as a model organism in which to study the visual cycle and the retinal degeneration that results from its disruption. One goal of this project is to further our understanding of the basis for the retinal degeneration that results from perturbation of the Drosophila visual cycle. This will be achieved by examining the effects of mutations disrupting genes that function in the visual cycle, using a combination of biochemical, cell biological and genetic approaches. A second goal of this project is to use genetic and biochemical approaches to test the newly formulated model for the Drosophila visual cycle. Given that the photopigment in human ipRGCs, melanopsin, also appears to be a bistable photopigment, the recently published and proposed studies raise the possilbility that an enzymatic visual cycle is also used in conjunction with human melanopsin. PUBLIC HEALTH RELEVANCE: Many diseases affecting the visual cycle lead to retinal degeneration. The goal of this project is to exploit molecular genetic approaches in the fruit fly o identify the underlying basis of retinal degeneration that result from defects in the visual cycle.