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
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
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
Jia, Lixia; Linder, Maurine E; Blumer, Kendall J (2011) Gi/o signaling and the palmitoyltransferase DHHC2 regulate palmitate cycling and shuttling of RGS7 family-binding protein. J Biol Chem 286:13695-703
Jayaraman, Muralidharan; Zhou, Hao; Jia, Lixia et al. (2009) R9AP and R7BP: traffic cops for the RGS7 family in phototransduction and neuronal GPCR signaling. Trends Pharmacol Sci 30:17-24
Gu, Steven; Anton, Annepa; Salim, Samina et al. (2008) Alternative translation initiation of human regulators of G-protein signaling-2 yields a set of functionally distinct proteins. Mol Pharmacol 73:1-11
Grabowska, D; Jayaraman, M; Kaltenbronn, K M et al. (2008) Postnatal induction and localization of R7BP, a membrane-anchoring protein for regulator of G protein signaling 7 family-Gbeta5 complexes in brain. Neuroscience 151:969-82
Blumer, Kendall J; Thorner, Jeremy (2007) An adrenaline (and gold?) rush for the GPCR community. ACS Chem Biol 2:783-6
Osei-Owusu, Patrick; Sun, Xiaoguang; Drenan, Ryan M et al. (2007) Regulation of RGS2 and second messenger signaling in vascular smooth muscle cells by cGMP-dependent protein kinase. J Biol Chem 282:31656-65
Drenan, Ryan M; Doupnik, Craig A; Jayaraman, Muralidharan et al. (2006) R7BP augments the function of RGS7*Gbeta5 complexes by a plasma membrane-targeting mechanism. J Biol Chem 281:28222-31
Kim, Kyoungtae; Galletta, Brian J; Schmidt, Kevin O et al. (2006) Actin-based motility during endocytosis in budding yeast. Mol Biol Cell 17:1354-63

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