The long-term goal of this project is to define mechanisms that govern signal transduction by G protein-coupled receptors (GPCRs). The focus of the present application is a class of developmentally-regulated, visual and nervous system-specific G?? dimers consisting of G?5, the most diverged and least understood G? family member, bound to the G?-like domain of any member of the RGS7 (R7) family of G protein regulators. R7-G?5 heterodimers bind R7BP, a novel palmitoylated SNARE-like protein. The central hypothesis of this application is that palmitate cycling on R7BP controls the localization and function of R7-G?5-R7BP complexes as regulators of neuronal structure and function. This project will test this hypothesis by employing interdisciplinary cell, molecular and electrophysiological assays that address the following Specific Aims: 1) identify mechanisms that regulate R7BP palmitate cycling and trafficking in primary neurons;2) determine how R7BP regulates the ability of R7- G?5 complexes to modulate synaptic transmission and the role of palmitoylation in these processes;and 3) identify signaling mechanisms whereby R7-G?5-R7BP complexes regulate neuronal development, plasticity and morphogenesis.
The efficacy of drugs currently used to treat chronic disorders of the central nervous system, such as Parkinson's disease, epilepsy, addiction, pain and depression, often is limited by side effects or the development of tolerance. Understanding the mechanisms that regulate drug action could lead to the identification of novel means of augmenting drug efficacy or specificity. This project advances this goal by elucidating new mechanisms controlling the action of protein complexes that regulate the action of cocaine and morphine, and probably other drugs that act via modulatory G protein- coupled receptors in the nervous system.
|Sun, Xianqiang; Singh, Sukrit; Blumer, Kendall J et al. (2018) Simulation of spontaneous G protein activation reveals a new intermediate driving GDP unbinding. Elife 7:|
|Onken, Michael D; Makepeace, Carol M; Kaltenbronn, Kevin M et al. (2018) Targeting nucleotide exchange to inhibit constitutively active G protein ? subunits in cancer cells. Sci Signal 11:|
|Scherer, Stephanie L; Cain, Matthew D; Kanai, Stanley M et al. (2017) Regulation of neurite morphogenesis by interaction between R7 regulator of G protein signaling complexes and G protein subunit G?13. J Biol Chem 292:9906-9918|
|Kanai, Stanley M; Edwards, Alethia J; Rurik, Joel G et al. (2017) Proteolytic degradation of regulator of G protein signaling 2 facilitates temporal regulation of Gq/11 signaling and vascular contraction. J Biol Chem 292:19266-19278|
|Osei-Owusu, Patrick; Blumer, Kendall J (2015) Regulator of G Protein Signaling 2: A Versatile Regulator of Vascular Function. Prog Mol Biol Transl Sci 133:77-92|
|Osei-Owusu, Patrick; Owens, Elizabeth A; Jie, Li et al. (2015) Regulation of Renal Hemodynamics and Function by RGS2. PLoS One 10:e0132594|
|Rensing, Derek T; Uppal, Sakshi; Blumer, Kendall J et al. (2015) Toward the Selective Inhibition of G Proteins: Total Synthesis of a Simplified YM-254890 Analog. Org Lett 17:2270-3|
|Oladipupo, Sunday S; Smith, Craig; Santeford, Andrea et al. (2014) Endothelial cell FGF signaling is required for injury response but not for vascular homeostasis. Proc Natl Acad Sci U S A 111:13379-84|
|Osei-Owusu, Patrick; Knutsen, Russell H; Kozel, Beth A et al. (2014) Altered reactivity of resistance vasculature contributes to hypertension in elastin insufficiency. Am J Physiol Heart Circ Physiol 306:H654-66|
|Jia, Lixia; Chisari, Mariangela; Maktabi, Mohammad H et al. (2014) A mechanism regulating G protein-coupled receptor signaling that requires cycles of protein palmitoylation and depalmitoylation. J Biol Chem 289:6249-57|
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