Abstract

This grant is requested to support a program in basic research directed at elucidating, at a molecular level, the nature and mode of functioning of the adrenergic receptors for catecholamines. Catecholamies such as norepinephrine and epinephrine are of vital importance in the hormonal control of the entire circulation. These compounds appear to act via stimulation of adenyl cyclase in cell membranes which is in turn mediated by binding to specific beta-adrenergic receptors.
The specific aims of these studies include: 1) the isolation, purification and characterization of adrenergic receptors from heart muscle and other tissues, and 2) delineation of the way in which receptors interact with adenyl cyclase, and 3) study of isolated receptors in disease states.
These aims will be achieved by studying the binding of radioactively labeled (negative) 3H alprenolol, a competitive beta-adrenergic antagonist, to cell membrane fragments isolated from heart muscle, and to specific proteins isolated and purified from these membranes. Detailed characterization of these receptor structures will ultimately permit evaluation of possible alterations in their structure and function in disease states such as hypertension, congestive heart failure, or in physiological processes such as aging.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL016037-13
Application #
3335112
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1976-09-01
Project End
1986-08-31
Budget Start
1985-09-01
Budget End
1986-08-31
Support Year
13
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
Duke University
Department
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705

  Publications

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
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; 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
Liu, Xiangyu; Ahn, Seungkirl; Kahsai, Alem W et al. (2017) Mechanism of intracellular allosteric ?2AR antagonist revealed by X-ray crystal structure. Nature 548:480-484
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

Showing the most recent 10 out of 302 publications