G protein-coupled receptors (GPCRs) mediate hormonal control of numerous signaling pathways, many of which are dynamically regulated. At the receptor level, regulation can occur via inhibition of GPCR/G protein coupling (desensitization), redistribution of cell surface receptors (trafficking), or receptor degradation (down-regulation). Two protein families, G protein-coupled receptor kinases (GRKs) and arrestins, play a critical role in these processes. GRKs specifically phosphorylate the activated GPCRs, which in turn pro- motes arrestin binding. Arrestin interaction has been directly linked to many regulatory processes including GPCR desensitization, trafficking, and signaling via non-receptor tyrosine kinase and MAP kinase pathways. In the previous grant period we focused on characterizing the interaction of arrestins with GPCRs;the role of arrestins in regulating GPCR trafficking;and the interaction of arrestins with additional proteins. During the course of this work we also initiated studies in C. elegans in an effort to better correlate the structure and function of arrestin with in vivo biology. In the present application, we propose to extend our efforts in two major directions. The first involves further defining the role of GPCRs in regulating arrestin function by characterizing a number of arrestin/protein interactions that we have recently identified. The second involves our continued use of C. elegans as a model system to better define the mechanism of arrestin function in vivo. These studies are aimed at addressing several important questions. Do GPCRs regulate interactions that contribute to the diverse nature of arrestin function? What interactions mediate arrestin function in vivo and how are such interactions regulated? Overall, our efforts will provide unique mechanistic insight into the biochemical, cellular and molecular function of arrestins and should prove useful in understanding diseases where GPCR signaling defects are observed. G protein-coupled receptors have been implicated in many diseases including cancer, HIV, hypertension, sensory defects, and various neuronal disorders, and are the target for -50% of the drugs currently on the market. This research is aimed at understanding arrestins, a family of proteins that play an essential role in controlling GPCR function.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37GM047417-16
Application #
7578947
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Dunsmore, Sarah
Project Start
1994-01-01
Project End
2011-02-28
Budget Start
2009-03-01
Budget End
2010-02-28
Support Year
16
Fiscal Year
2009
Total Cost
$546,612
Indirect Cost
Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
053284659
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Komolov, Konstantin E; Benovic, Jeffrey L (2018) G protein-coupled receptor kinases: Past, present and future. Cell Signal 41:17-24
Luo, Jiansong; Busillo, John M; Stumm, Ralf et al. (2017) G Protein-Coupled Receptor Kinase 3 and Protein Kinase C Phosphorylate the Distal C-Terminal Tail of the Chemokine Receptor CXCR4 and Mediate Recruitment of ?-Arrestin. Mol Pharmacol 91:554-566
Carr 3rd, Richard; Koziol-White, Cynthia; Zhang, Jie et al. (2016) Interdicting Gq Activation in Airway Disease by Receptor-Dependent and Receptor-Independent Mechanisms. Mol Pharmacol 89:94-104
Carr 3rd, Richard; Schilling, Justin; Song, Jianliang et al. (2016) ?-arrestin-biased signaling through the ?2-adrenergic receptor promotes cardiomyocyte contraction. Proc Natl Acad Sci U S A 113:E4107-16
Carr 3rd, Richard; Benovic, Jeffrey L (2016) From biased signalling to polypharmacology: unlocking unique intracellular signalling using pepducins. Biochem Soc Trans 44:555-61
Tian, Xufan; Irannejad, Roshanak; Bowman, Shanna L et al. (2016) The ?-Arrestin ARRDC3 Regulates the Endosomal Residence Time and Intracellular Signaling of the ?2-Adrenergic Receptor. J Biol Chem 291:14510-25
Tian, Xufan; Kang, Dong Soo; Benovic, Jeffrey L (2014) ?-arrestins and G protein-coupled receptor trafficking. Handb Exp Pharmacol 219:173-86
Kang, Dong Soo; Tian, Xufan; Benovic, Jeffrey L (2014) Role of ?-arrestins and arrestin domain-containing proteins in G protein-coupled receptor trafficking. Curr Opin Cell Biol 27:63-71
Kook, S; Zhan, X; Cleghorn, W M et al. (2014) Caspase-cleaved arrestin-2 and BID cooperatively facilitate cytochrome C release and cell death. Cell Death Differ 21:172-84
Carr 3rd, Richard; Du, Yang; Quoyer, Julie et al. (2014) Development and characterization of pepducins as Gs-biased allosteric agonists. J Biol Chem 289:35668-84

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