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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM044592-21
Application #
8231553
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Dunsmore, Sarah
Project Start
1990-07-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2014-03-31
Support Year
21
Fiscal Year
2012
Total Cost
$573,315
Indirect Cost
$196,134
Name
Washington University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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
Cain, Matthew D; Vo, Bradly Q; Kolesnikov, Alexander V et al. (2013) An allosteric regulator of R7-RGS proteins influences light-evoked activity and glutamatergic waves in the inner retina. PLoS One 8:e82276
Osei-Owusu, Patrick; Sabharwal, Rasna; Kaltenbronn, Kevin M et al. (2012) Regulator of G protein signaling 2 deficiency causes endothelial dysfunction and impaired endothelium-derived hyperpolarizing factor-mediated relaxation by dysregulating Gi/o signaling. J Biol Chem 287:12541-9
Zhou, Hao; Chisari, Mariangela; Raehal, Kirsten M et al. (2012) GIRK channel modulation by assembly with allosterically regulated RGS proteins. Proc Natl Acad Sci U S A 109:19977-82
Chakir, Khalid; Zhu, Weizhong; Tsang, Sharon et al. (2011) RGS2 is a primary terminator of β₂-adrenergic receptor-mediated G(i) signaling. J Mol Cell Cardiol 50:1000-7

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