Adenosine receptors in the myocardium are known to play an important role in cardiac function in both the normal and diseased heart. Prior studies in this laboratory have focused on the cellular responses elicited upon stimulation of these receptors. In addition studies have been initiated to investigate how the receptor signals are translated into cellular responses in the heart. However, little is known regarding the details of the mechanisms involved in the elicited responses and the cross-regulation between cardiac adenosine receptors. We and others have reported that adenosine A1 receptor (A1R), adenosine A2A receptor (A2AR) and ?1 adrenergic receptor (?1 R) stimulation results in a number of effects in ventricular myocytes. The A1R serves an important antiadrenergic action, and the A2AR causes a positive inotropic response. Furthermore, together, the A2AR attenuates the A1 R-mediated antiadrenergic actions. However, little is known about the molecular events involved in adenosine receptor signal transduction mechanisms and interaction of the A1R and A2AR including the adenosine A3 receptor (A3R). Thus, the objective of this project will be to determine the molecular signal transduction mechanisms involving protein kinases and phosphatases in the A1R-, A2AR- and A3R-mediated actions in the heart. In addition the operation of these adenosine receptors in regulating cardiac mechanical and metabolic function will be determined. Using rat and A1 R, A2AR and double (A1R+A2AR) knockout mice ventricular myocytes, myocyte membranes and perfused hearts, the proposed studies should reveal: 1) Whether A1R stimulation causes protein kinase C isoforms to translocate and bind to RACK (receptor activated C kinase) proteins of the myocardial sarcolemma. Also the involvement of p38-MAPK (mitogen activated protein kinase) in the A1 R-mediated antiadrenergic action will be investigated, 2) The importance of the antiadrenergic action resulting from A3R stimulation and whether PKC isoforms are involved, 3) The way in which A2AR inhibits A1R mediated cardiac antiadrenergic actions, 4) The effect and importance of protein phosphatases in the cardiac effects produced by A1R, A2AR and A3R stimulation, and 5) How myocardial hypoxia and/or ischemia modifies the function of A1 R, A2AR and/or A3R, thereby increasing or reducing their roles in modulating heart function. The results obtained from these studies will provide new information regarding the molecular functioning of adenosine receptors in the myocardium. Additionally, the findings should significantly contribute to our knowledge of the molecular mechanisms of G- protein coupled receptor operation in the normal and diseased heart. Such information should be instrumental for the development of new therapies and agents to alleviate cardiac dysfunction.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL084160-03
Application #
7633118
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Liang, Isabella Y
Project Start
2007-07-11
Project End
2011-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
3
Fiscal Year
2009
Total Cost
$406,250
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Physiology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Komatsu, Satoshi; Dobson Jr, James G; Ikebe, Mitsuo et al. (2012) Crosstalk between adenosine A1 and ?1-adrenergic receptors regulates translocation of PKC? in isolated rat cardiomyocytes. J Cell Physiol 227:3201-7
Fenton, Richard A; Shea, Lynne G; Doddi, Cecilia et al. (2010) Myocardial adenosine A(1)-receptor-mediated adenoprotection involves phospholipase C, PKC-epsilon, and p38 MAPK, but not HSP27. Am J Physiol Heart Circ Physiol 298:H1671-8
Fenton, Richard A; Komatsu, Satoshi; Ikebe, Mitsuo et al. (2009) Adenoprotection of the heart involves phospholipase C-induced activation and translocation of PKC-epsilon to RACK2 in adult rat and mouse. Am J Physiol Heart Circ Physiol 297:H718-25
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