The long-term goal of the proposed research is to understand the molecular mechanisms underlying phototransduction in the frutifly, Drosophila melanogaster. Most of the proteins that function in Drosophila phototransduction are coupled into a supramolecular signaling complex, referred to as the signalplex. The central protein in the signalplex is a PDZ protein referred to as INAD. The signalplex represents the first example of a G-protein coupled signaling cascade that is linked in a large macromolecular assembly. However, recent evidence indicates that similar G-protein coupled signaling complexes exist in mammalian cells. Nevertheless, characterization of the composition, assembly and functions of these complexes in native tissues has been limited. The Drosophila visual system offers a tractable in vivo model for characterizing a G-protein coupled signaling complex, using a combination of genetics, biochemistry, molecular biology, cell biology and electrophysiology. The first specific aim of the proposed research is to characterize novel molecular mechanisms regulating a new member of the signalplex, Arrestin2. Arrestin2 is of particular interest since recent studies indicate that, in addition to functioning in inactivation of the receptor, abnormally stable rhodopsin/arrestin complexes contribute to one form of retinal degeneration. We propose to investigate the role of the INAD/ Arrestin2 interaction and to test the hypothesis that arrestins are regulated by phosphoinositides. One INAD binding protein is protein kinase C (PKC) and interaction of PKC with INAD could provide a mechanism for rapid light-dependent regulation of PKC substrates, which also associate with the signalplex. However, the substrates and mechanisms regulated by light-dependent PKC phosphorylation are poorly understood. In the second specific aim, we propose to test the hypothesis that the G-alpha-q, which transiently interacts with the signalplex, is phosphorylated by PKC and this modification regulates its GTPase activity. The goal of the third specific aim is to test the hypothesis that PKC phosphorylation of INAD regulates dynamic INAD/target protein interactions. The fourth specific aim is concerned with characterizing the mechanisms regulating the localization of the signalplex. Several of the proteins that are the focus of the proposed research are related to proteins that function in mammalian phototransduction and, if mutated, result in retinal degeneration. Therefore, the proposed studies should contribute to a general understanding of the mechanisms regulating phototransduction, as well as provide new insights into the mechanisms underlying certain forms of retinal degeneration.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Special Emphasis Panel (ZRG1-VISC (01))
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Mariani, Andrew P
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Johns Hopkins University
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Liu, Jiangqu; Sokabe, Takaaki; Montell, Craig (2018) A Temperature Gradient Assay to Determine Thermal Preferences of Drosophila Larvae. J Vis Exp :
Leung, Nicole Y; Montell, Craig (2017) Unconventional Roles of Opsins. Annu Rev Cell Dev Biol 33:241-264
Ni, Jinfei D; Baik, Lisa S; Holmes, Todd C et al. (2017) A rhodopsin in the brain functions in circadian photoentrainment in Drosophila. Nature 545:340-344
Sokabe, Takaaki; Chen, Hsiang-Chin; Luo, Junjie et al. (2016) A Switch in Thermal Preference in Drosophila Larvae Depends on Multiple Rhodopsins. Cell Rep 17:336-344
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
Walker, Marquis T; Montell, Craig (2016) Suppression of the motor deficit in a mucolipidosis type IV mouse model by bone marrow transplantation. Hum Mol Genet 25:2752-2761
Walker, Marquis T; Rupp, Alan; Elsaesser, Rebecca et al. (2015) RdgB2 is required for dim-light input into intrinsically photosensitive retinal ganglion cells. Mol Biol Cell 26:3671-8
Chen, Zijing; Chen, Hsiang-Chin; Montell, Craig (2015) TRP and Rhodopsin Transport Depends on Dual XPORT ER Chaperones Encoded by an Operon. Cell Rep 13:573-584
Liu, Chao; Montell, Craig (2015) Forcing open TRP channels: Mechanical gating as a unifying activation mechanism. Biochem Biophys Res Commun 460:22-5
Akitake, Bradley; Ren, Qiuting; Boiko, Nina et al. (2015) Coordination and fine motor control depend on Drosophila TRP?. Nat Commun 6:7288

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