The G protein-coupled receptors (GPCRs) comprise a broad family of receptors that activate a large number of effectors in response to a variety of signals that include amines, photons, lipids peptides and proteases. Signaling through GPCRs requires the coordinated balance between processes that govern receptor activation, desensitization and resensitization. Desensitization of GPCRs involves receptor phosphorylation by specific G protein-coupled receptor kinases (GRKs) and interactions with arrestin proteins. GRKs and arrestins desensitize the second messenger signaling function of GPCRs and also initiate the internalization of desensitized GPCRs to re-establish normal responsiveness. In addition, GRKs and arrestins may contribute to novel GPCR signaling paradigms. The overall objective of the proposed research is to define the basic molecular and cellular mechanisms that contribute to these processes with the goal of better understanding physiological and pathological conditions. The dopamine and adrenergic receptors will be used as the prototypic GPCRs since these receptors control a wide variety of function that include vascular tone, cardiac function, and endocrine secretion to complex behaviors such as locomotion, cognition and affect.
Aim I : Real-time dynamic assays will be used to follow activation and desensitization of GPCRs and assess the selectivity and structure-function of various members of the GRK and arrestin families.
Aim II : The molecular and cellular basis of GPCR internalization and resensitization. as well as the role of GRKs and arrestins in these processes, will also be examined.
Aim III : The molecular basis and physiological relevance of the emerging signaling function of the GPCR/GRK/betaarrestin complexes will be examined in cellular and transgenic animal systems.
Aim I V: Using the above paradigms and genetically engineered knockout animals, the signaling properties and physiological role of members of the D2 dopamine receptor family will be investigated. The biochemical, pharmacological, physiological, and gene-targeting approaches derived from this work should broaden our understanding of the role of the GPCRs in normal physiology and disease and they may provide new insights into novel therapeutic approaches for treating conditions as diverse as hear failure, drug abuse, and psychiatric disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
3R01NS019576-17S1
Application #
6322922
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
Kitt, Cheryl A
Project Start
1983-12-01
Project End
2003-11-30
Budget Start
1999-12-01
Budget End
2000-11-30
Support Year
17
Fiscal Year
2000
Total Cost
$50,000
Indirect Cost
Name
Duke University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Marion, S├ębastien; Urs, Nikhil M; Peterson, Sean M et al. (2014) Dopamine D2 receptor relies upon PPM/PP2C protein phosphatases to dephosphorylate huntingtin protein. J Biol Chem 289:11715-24
Philipp, Melanie; Berger, Ina M; Just, Steffen et al. (2014) Overlapping and opposing functions of G protein-coupled receptor kinase 2 (GRK2) and GRK5 during heart development. J Biol Chem 289:26119-30
Burkhalter, Martin D; Fralish, Gregory B; Premont, Richard T et al. (2013) Grk5l controls heart development by limiting mTOR signaling during symmetry breaking. Cell Rep 4:625-32
Philipp, Melanie; Evron, Tama; Caron, Marc G (2013) The role of arrestins in development. Prog Mol Biol Transl Sci 118:225-42
Evron, Tama; Daigle, Tanya L; Caron, Marc G (2012) GRK2: multiple roles beyond G protein-coupled receptor desensitization. Trends Pharmacol Sci 33:154-64
Evron, Tama; Philipp, Melanie; Lu, Jiuyi et al. (2011) Growth Arrest Specific 8 (Gas8) and G protein-coupled receptor kinase 2 (GRK2) cooperate in the control of Smoothened signaling. J Biol Chem 286:27676-86
Berlanga, M L; Price, D L; Phung, B S et al. (2011) Multiscale imaging characterization of dopamine transporter knockout mice reveals regional alterations in spine density of medium spiny neurons. Brain Res 1390:41-9
Ramsey, Amy J; Milenkovic, Marija; Oliveira, Ana F et al. (2011) Impaired NMDA receptor transmission alters striatal synapses and DISC1 protein in an age-dependent manner. Proc Natl Acad Sci U S A 108:5795-800
Sotnikova, Tatyana D; Beaulieu, Jean-Martin; Espinoza, Stefano et al. (2010) The dopamine metabolite 3-methoxytyramine is a neuromodulator. PLoS One 5:e13452
Abbas, Atheir I; Yadav, Prem N; Yao, Wei-Dong et al. (2009) PSD-95 is essential for hallucinogen and atypical antipsychotic drug actions at serotonin receptors. J Neurosci 29:7124-36

Showing the most recent 10 out of 132 publications