Abstract

3 Adrenoceptors (pARs) signaling is finely regulated to control cardiovascular function in response to sympathetic nervous system input (norepinephrine) and to adrenaline (epinephrine) from the adrenal gland. In animal hearts, two highly homologous pARs (P1AR and P2AR) are stimulated by catecholamines to enhance contractility and heart rate. Chronic stimulation of cardiac (3ARs by elevated circulating catecholamines as well as decreased cardiac (31AR density is clinically associated with heart failure. The primary functions attributed to GPCRs are ligand binding and G-protein coupling. However, the specific and diversified functional properties of GPCRs in vivo involve kinetic receptor conformational changes for binding different partners in signaling complexes, and the localization of receptor signaling complexes in cell type- specific manner. We hypothesize that norepinephrine and epinephrine can activate distinct signaling pathways for both (31AR and (32AR in cardiac myocyte. We have chosen the neonatal cardiac myocyte isolated from the PAR gene deficiency mice as a model system to study the functional roles of ligand- receptor interactions in differentiated cells. The goals of this proposal are (1) to characterize (31 AR and |32AR subtype-specific signaling by different agonists in neonatal myocytes, (2) define the cellular and biochemical properties of (31 AR and P2AR under norepinephrine and epinephrine stimulation in cardiac myocytes, (3) to characterize the subcellular distribution of (31ARand (32AR, and other signaling molecules under norepinephrine and epinephrine stimulation in cardiac myocyte, (4) to identify receptor interaction domains and their targeted proteins, and to characterize the receptor signaling complex formation and stability upon agonist stimulation. A better understanding of agonist-induced PAR conformationchange for the organization of signaling complexes may facilitate new drug designs and suggest new clinical applications in treating various cardiovascular diseases.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL082846-05
Application #
7760985
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Liang, Isabella Y
Project Start
2006-02-01
Project End
2010-12-14
Budget Start
2010-02-01
Budget End
2010-12-14
Support Year
5
Fiscal Year
2010
Total Cost
$292,270
Indirect Cost

  Institution

Name
University of Illinois Urbana-Champaign
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820

  Publications

Zhao, Hongyu; Shen, Ao; Xiang, Yang K et al. (2016) Three Recombinant Engineered Antibodies against Recombinant Tags with High Affinity and Specificity. PLoS One 11:e0150125
Skieterska, Kamila; Shen, Ao; Clarisse, Dorien et al. (2016) Characterization of the interaction between the dopamine D4 receptor, KLHL12 and ?-arrestins. Cell Signal 28:1001-14
Barbagallo, Federica; Xu, Bing; Reddy, Gopireddy R et al. (2016) Genetically Encoded Biosensors Reveal PKA Hyperphosphorylation on the Myofilaments in Rabbit Heart Failure. Circ Res 119:931-43
Fu, Qin; Xiang, Yang K (2015) Trafficking of ?-Adrenergic Receptors: Implications in Intracellular Receptor Signaling. Prog Mol Biol Transl Sci 132:151-88
Fu, Qin; Xu, Bing; Parikh, Dippal et al. (2015) Insulin induces IRS2-dependent and GRK2-mediated ?2AR internalization to attenuate ?AR signaling in cardiomyocytes. Cell Signal 27:707-15
Fu, Qin; Xu, Bing; Liu, Yongming et al. (2014) Insulin inhibits cardiac contractility by inducing a Gi-biased ?2-adrenergic signaling in hearts. Diabetes 63:2676-89
Nooh, Mohammed M; Naren, Anjaparavanda P; Kim, Sung-Jin et al. (2013) SAP97 controls the trafficking and resensitization of the beta-1-adrenergic receptor through its PDZ2 and I3 domains. PLoS One 8:e63379
Fu, Qin; Chen, Xiongwen; Xiang, Yang K (2013) Compartmentalization of ?-adrenergic signals in cardiomyocytes. Trends Cardiovasc Med 23:250-6
Lim, Ji-Hong; Gerhart-Hines, Zachary; Dominy, John E et al. (2013) Oleic acid stimulates complete oxidation of fatty acids through protein kinase A-dependent activation of SIRT1-PGC1? complex. J Biol Chem 288:7117-26
Liu, Shubai; Li, Ying; Kim, Sungjin et al. (2012) Phosphodiesterases coordinate cAMP propagation induced by two stimulatory G protein-coupled receptors in hearts. Proc Natl Acad Sci U S A 109:6578-83

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