Drosophila vision is the first sensory system subjected to detailed genetic analyses and serves as a paradigm for other sensory modalities. The major fly rhodopsin, Rh1, is a visual pigment comprised of a retinal chromophore covalently bound to an opsin protein, and functions primarily in photoreceptor cells. The proposed work has relevance for mammalian rhodopsins, especially melanopsin, which is expressed in intrinsically photosensitive retinal ganglion cells (ipRGCs). Our current knowledge of phototransduction in ipRGCs has been greatly accelerated by the work in flies, but many questions remain regarding the modulatory and regulatory steps of melanopsin-driven phototransduction. Investigating rhodopsin-interacting proteins in flies is a powerful approach to identify novel molecular components required for phototransduction and rhodopsin homeostasis. Here, we exploit the unparalleled suite of tools available in Drosophila to discover the functions of previously unsuspected Rh1-interacting proteins. The proposed work focuses on dissecting the functions of two new types of Rh1-interacting proteins. One of these proteins is an orphan GPCR, known as Bride-of-Sevenless (BOSS), which we found associates with rhodopsin.
In Aim 1, we test the idea that BOSS heterodimerizes with rhodopsin, and this interaction is required for phototransduction. Understanding the functional significance of GPCR heterodimerization has potential clinical relevance, as GPCRs are the molecular targets for numerous therapeutic drugs.
Aim 2 builds on our recent preliminary data indicating that an ATP-binding cassette (ABC) transporter, ABCH1, associates with Rh1 and is critical for phototransduction and the prevention of retinal degeneration. ABCH1 belongs to the largely uncharacterized ABCH subfamily and may play a role in chromophore transport, rhodopsin stability, and photoreceptor cell maintenance. ABC transporters are well established in vertebrates for their role in drug resistance, but less is known about their role in the transport of endogenous and exogenous substances in invertebrates. This work will provide the conceptual framework for clarifying molecular mechanisms regulating mammalian melanopsins, which are the light sensors in ipRGCs and bear greater similarities to Drosophila rhodopsins, than the visual pigments in rods and cones.
The proposed work to characterize novel rhodopsin-interacting proteins required for phototransduction in Drosophila has relevance for melanopsins in intrinsically photosensitive retinal ganglion cells (ipRGCs). Not much is known about ipRGC function in retinal and optic nerve disease, with emerging research providing evidence for their role in diabetes, retinitis pigmentosa, glaucoma, and hereditary optic neuropathy. The use of an animal model to discover new molecular mechanisms regulating melanopsins is critical for understanding disease etiology and valuable for developing new strategies for therapy.
| Leung, Nicole Y; Montell, Craig (2017) Unconventional Roles of Opsins. Annu Rev Cell Dev Biol 33:241-264 |
| Hofmann, Lukas; Tsybovsky, Yaroslav; Alexander, Nathan S et al. (2016) Structural Insights into the Drosophila melanogaster Retinol Dehydrogenase, a Member of the Short-Chain Dehydrogenase/Reductase Family. Biochemistry 55:6545-6557 |
