G protein-coupled receptors (GPCRs) and their signaling pathways are the targets of many current therapeutics as well as drugs of abuse. Most currently used therapeutics were developed decades ago when few components of GPCR signaling systems were known. However, new therapeutics, such as agonists biased to evoke GPCR-arrestin signaling, are being developed as a consequence of identifying novel components and regulators of GPCR signaling networks. Such novel targets potentially enable long-standing problems associated with current therapeutics, such as drug tolerance, side effects or addiction, to be reduced or eliminated. This project addresses these long-term goals by identifying novel mechanisms that control GPCR signaling in the nervous system. It focuses on the R7 RGS family of G protein regulators, which have been shown genetically to be critical intracellular regulators of GPCR signaling throughout the nervous system, and which regulate the biological effects of opioids and amphetamines, and side effects of L-DOPA.
The Aims will determine how R7 RGS proteins under the control of a palmitoylated allosteric regulator called R7BP (R7 RGS-binding protein) regulate the activity of adenylyl cyclases and cAMP signaling in neuronal cells. They will identify novel enzymes that regulate palmitate turnover on R7BP and establish the functions of these enzymes as regulators of GPCR signaling in neuronal cells. Lastly, they will determine whether global or local cycles of palmitate turnover regulate the intracellular trafficking and function of R7BP-bound R7 RGS complexes. New knowledge gained by this project will provide deeper understanding of neurobiological signaling processes controlled by R7 RGS proteins, new models for elucidating the functions of palmitate turnover in diverse aspects of cell signaling and disease, and new drug targets that potentially enhance the action or reduce the side effects of GPCR-targeted neurotherapeutics.

Public Health Relevance

Drug tolerance and side effects limit use of many therapeutic agents, including opioids in chronic pain and L- DOPA in Parkinson's disease. To improve clinical utility of therapeutics, investigators must identify molecular and cellular mechanisms tha regulate drug action to discover means of blunting or eliminating tolerance or dose-limiting side effects. These objectives will be addressed in this project by identifying molecular and cellular mechanisms that regulate the action of drugs that target G protein-coupled receptors in the nervous system. Enzymes controlling these mechanisms will be identified to establish them as new drug targets, potentially for enhancing opioid analgesia or reducing side effects of L-DOPA in Parkinson's disease.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01GM044592-22
Application #
8775574
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Dunsmore, Sarah
Project Start
Project End
Budget Start
Budget End
Support Year
22
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Washington University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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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
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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
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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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