Norepinephrine (NE) and epinephrine (EPI) act through alpha and beta-adrenergic receptors (AR) subtypes coupled to hetero-trimeric G proteins to control the circulation. Several important mechanisms regulating receptor function involve phosphorylation by PKA, PKC or GRKs such as betaARK. Phosphorylation promotes binding of beta-arrestin to the receptors leading to their desensitization. Abnormal function of these regulatory mechanisms may contribute to cardiomyopathy and congestive heart failure. Recent evidence suggests that several aspects of signaling by beta-ARs and other GPCRs are not readily explainable by their effects on second messengers, including activation of MAP kinase cascades. This proposal has three aims which focus on elucidating novel mechanisms regulating signaling through beta-ARs and other GPCRs, targeting the receptors, the kinases which phosphorylate them, and the beta-arrestins which bind to them. The goals are to elucidate 1) how the receptors activate mitogenic and other signaling pathways by novel mechanisms, forming complexes with receptor tyrosine kinases and SH3 domain containing proteins; 2) novel ways in which PKA and GRKs regulate receptor function. The physiology of GRK action will be probed in vivo with knockout animals; 3) new roles for beta-arrestins in regulation and signaling. Novel interactions of beta-arrestin with the kinases cSrc, JNK3 and ASK as well as with other binding partners will be investigated and the physiology of beta-arrestin explored with knockout animals. Understanding of the regulation of beta-ARs may point toward novel therapeutic strategies for cardiovascular diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Study Section
Pharmacology A Study Section (PHRA)
Program Officer
Reinlib, Leslie
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Duke University
Internal Medicine/Medicine
Schools of Medicine
United States
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Kim, Jihee; Grotegut, Chad A; Wisler, James W et al. (2018) ?-arrestin 1 regulates ?2-adrenergic receptor-mediated skeletal muscle hypertrophy and contractility. Skelet Muscle 8:39
Wisler, James W; Rockman, Howard A; Lefkowitz, Robert J (2018) Biased G Protein-Coupled Receptor Signaling: Changing the Paradigm of Drug Discovery. Circulation 137:2315-2317
Ahn, Seungkirl; Pani, Biswaranjan; Kahsai, Alem W et al. (2018) Small-Molecule Positive Allosteric Modulators of the ?2-Adrenoceptor Isolated from DNA-Encoded Libraries. Mol Pharmacol 94:850-861
Staus, Dean P; Wingler, Laura M; Choi, Minjung et al. (2018) Sortase ligation enables homogeneous GPCR phosphorylation to reveal diversity in ?-arrestin coupling. Proc Natl Acad Sci U S A 115:3834-3839
Smith, Jeffrey S; Lefkowitz, Robert J; Rajagopal, Sudarshan (2018) Biased signalling: from simple switches to allosteric microprocessors. Nat Rev Drug Discov 17:243-260
Stoppel, Laura J; Auerbach, Benjamin D; Senter, Rebecca K et al. (2017) ?-Arrestin2 Couples Metabotropic Glutamate Receptor 5 to Neuronal Protein Synthesis and Is a Potential Target to Treat Fragile X. Cell Rep 18:2807-2814
Cahill 3rd, Thomas J; Thomsen, Alex R B; Tarrasch, Jeffrey T et al. (2017) Distinct conformations of GPCR-?-arrestin complexes mediate desensitization, signaling, and endocytosis. Proc Natl Acad Sci U S A 114:2562-2567
Rein, Lindsay Am; Wisler, James W; Kim, Jihee et al. (2017) ?-Arrestin2 mediates progression of murine primary myelofibrosis. JCI Insight 2:
Ahn, Seungkirl; Kahsai, Alem W; Pani, Biswaranjan et al. (2017) Allosteric ""beta-blocker"" isolated from a DNA-encoded small molecule library. Proc Natl Acad Sci U S A 114:1708-1713
Paek, Jaeho; Kalocsay, Marian; Staus, Dean P et al. (2017) Multidimensional Tracking of GPCR Signaling via Peroxidase-Catalyzed Proximity Labeling. Cell 169:338-349.e11

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