Myocardial Adenosine Receptors

心肌腺苷受体

• 批准号: 7868038
• 负责人: JAMES G DOBSON
• 金额: $ 40.63万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-11 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7868038
• 关键词: Adenosine; Adenosine A1 Receptor; Adenosine A2A Receptor; Adenosine A3 Receptor; Adrenergic Antagonists; Adrenergic Receptor; Affect; Attenuated; Binding; Biochemical; Cardiac; Cardiac Myocytes; Development; Doctor of Philosophy; Ensure; Event; Functional disorder; G-Protein-Coupled Receptors; Heart; Ischemia; Knockout Mice; Knowledge; Laboratories; Mechanics; Mediating; Membrane; Metabolic; Mitogen-Activated Protein Kinases; Modification; Molecular; Muscle Cells; Myocardial; Myocardium; Pathway interactions; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Protein Isoforms; Protein Kinase; Protein Kinase C; Protein phosphatase; Proteins; Purinergic P1 Receptors; Rattus; Receptor Signaling; Regulation; Reporting; Role; Sarcolemma; Signal Pathway; Signal Transduction; Tissues; Translating; Ventricular; design; heart function; human MAPK14 protein; myocardial hypoxia; operation; protein kinase C epsilon; receptor; receptors for activated C kinase; response

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：已知心肌中的腺苷受体在正常心脏和患病心脏的心脏功能中发挥重要作用。该实验室之前的研究主要集中在刺激这些受体时引发的细胞反应。此外，还开始研究受体信号如何转化为心脏中的细胞反应。然而，人们对引起的反应和心脏腺苷受体之间的交叉调节所涉及的机制细节知之甚少。我们和其他人报道了腺苷 A1 受体 (A1R)、腺苷 A2A 受体 (A2AR) 和 ?1 肾上腺素能受体 (?1 R) 刺激会对心室肌细胞产生多种影响。 A1R 具有重要的抗肾上腺素能作用，A2AR 会引起正性肌力反应。此外，A2AR 共同减弱 A1 R 介导的抗肾上腺素能作用。然而，人们对腺苷受体信号转导机制以及 A1R 和 A2AR（包括腺苷 A3 受体 (A3R)）之间的相互作用所涉及的分子事件知之甚少。因此，该项目的目标是确定心脏中 A1R、A2AR 和 A3R 介导作用中涉及蛋白激酶和磷酸酶的分子信号转导机制。此外，还将确定这些腺苷受体在调节心脏机械和代谢功能中的作用。使用大鼠和 A1R、A2AR 和双 (A1R+A2AR) 敲除小鼠心室肌细胞、肌细胞膜和灌注心脏，拟议的研究应揭示：1) A1R 刺激是否会导致蛋白激酶 C 亚型易位并与心肌肌膜的 RACK（受体激活 C 激酶）蛋白结合。还将研究 p38-MAPK（丝裂原激活蛋白激酶）在 A1 R 介导的抗肾上腺素能作用中的参与，2）A3R 刺激产生的抗肾上腺素能作用的重要性以及 PKC 亚型是否参与，3）A2AR 抑制 A1R 介导的心脏抗肾上腺素能作用的方式，4）蛋白质的作用和重要性 A1R、A2AR 和 A3R 刺激产生的心脏效应中的磷酸酶，以及 5) 心肌缺氧和/或缺血如何改变 A1R、A2AR 和/或 A3R 的功能，从而增加或减少它们在调节心脏功能中的作用。这些研究获得的结果将提供有关心肌中腺苷受体分子功能的新信息。此外，这些发现应该极大地有助于我们了解正常和患病心脏中 G 蛋白偶联受体运作的分子机制。这些信息应该有助于开发缓解心脏功能障碍的新疗法和药物。