(Verbatim from the application): Adenosine receptors play an important role in regulating cardiac function. For example, adenosine Al receptors affect heart rhythm, contraction and metabolism and mediate ischemic preconditioning. Adenosine by interacting with adenosine Al receptors is known to be antiadrenergic in that it reduces the contractile and metabolic responsiveness of the myocardium to beta1-adrenergic stimulation. Stimulation of adenosine A2a receptors has been reported to directly increase cardiac contractility. Recently we reported that adenosine A2a receptor stimulation also limits the antiadrenergic actions of adenosine. The mechanism by which the cardiac adenosine A2a receptors affect adenosine Al receptor function is not known. Furthermore, it is not known if A2a receptor actions also effect functioning of other receptors such as muscarinic receptor functioning. The objective of this project is to investigate the molecular mechanisms by which the adenosine A2a receptor inhibits adenosine Al receptor mediated antiadrenergic actions in the heart. Using rat ventricular myocytes and myocyte membranes, the proposed studies should reveal: 1) The way in which adenosine A2a receptor activation inhibits the antiadrenergic actions resulting from adenosine Al and muscarine M2 receptor stimulation, 2) The effect of adenosine A2a receptor action on f3 1-adrenergic, and adenosine Al ligand binding and beta1-adrenergic receptor sensitive adenylyl cyclase activity, 3) The importance of protein kinases A and C, G protein kinases, and receptor phosphorylation in the adenosine A2a receptor-mediated inhibition of adenosine Al-elicited antiadrenergic actions, and 4) The action of adenosine A2a receptor activation on adenosine Al receptor-mediated changes in GTPase activity upon beta1-adrenergic receptor stimulation. The results obtained from these studies should provide new information regarding the molecular functioning of adenosine receptors in the myocardium. Additionally, the findings should significantly contribute to our basic knowledge of the molecular mechanisms of G protein coupled receptor cross-regulation in the heart.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066045-02
Application #
6499100
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Balshaw, David M
Project Start
2001-02-05
Project End
2005-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
2
Fiscal Year
2002
Total Cost
$355,876
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Physiology
Type
Schools of Medicine
DUNS #
660735098
City
Worcester
State
MA
Country
United States
Zip Code
01655
Dobson Jr, James G; Shea, Lynne G; Fenton, Richard A (2008) Adenosine A2A and beta-adrenergic calcium transient and contractile responses in rat ventricular myocytes. Am J Physiol Heart Circ Physiol 295:H2364-72
Tikh, Eugene I; Fenton, Richard A; Chen, Jiang-Fan et al. (2008) Adenosine A1 and A2A receptor regulation of protein phosphatase 2A in the murine heart. J Cell Physiol 216:83-90
Fenton, Richard A; Dobson Jr, James G (2007) Adenosine A1 and A2A receptor effects on G-protein cycling in beta-adrenergic stimulated ventricular membranes. J Cell Physiol 213:785-92
Tikh, Eugene I; Fenton, Richard A; Dobson Jr, James G (2006) Contractile effects of adenosine A1 and A2A receptors in isolated murine hearts. Am J Physiol Heart Circ Physiol 290:H348-56
Fenton, Richard A; Dickson, Eric W; Dobson Jr, James G (2005) Inhibition of phosphatase activity enhances preconditioning and limits cell death in the ischemic/reperfused aged rat heart. Life Sci 77:3375-88
Lorbar, Mojca; Chung, Eugene S; Nabi, Arash et al. (2004) Receptors subtypes involved in adenosine-mediated modulation of norepinephrine release from cardiac nerve terminals. Can J Physiol Pharmacol 82:1026-31
Dobson Jr, James G; Fray, John; Leonard, Jack L et al. (2003) Molecular mechanisms of reduced beta-adrenergic signaling in the aged heart as revealed by genomic profiling. Physiol Genomics 15:142-7
Dobson Jr, James G; Shea, Lynne G; Fenton, Richard A (2003) Beta-adrenergic and antiadrenergic modulation of cardiac adenylyl cyclase is influenced by phosphorylation. Am J Physiol Heart Circ Physiol 285:H1471-8