Myocardial Adenosine Receptors

心肌腺苷受体

• 批准号: 7633118
• 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 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7633118
• 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; Operative Surgical Procedures; 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; 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）：众所周知，心肌中的腺苷受体在正常和患病心脏的心脏功能中起重要作用。该实验室的先前研究集中在刺激这些受体后引起的细胞反应上。此外，已经开始研究研究受体信号如何转化为心脏中的细胞反应。但是，关于引起反应中涉及的机制的细节以及心脏腺苷受体之间的交叉调节知之甚少。我们和其他人报告说，腺苷A1受体（A1R），腺苷A2A受体（A2AR）和1腺能受体（？1 R）刺激会导致心室肌细胞的许多作用。 A1R发挥了重要的抗氧化作用，A2AR会引起阳性的肌力反应。此外，A2AR一起减轻了A1 r介导的抗氧化作用。然而，对于腺苷受体信号转导机制涉及的分子事件以及A1R和A2AR的相互作用，包括腺苷A3受体（A3R），知之甚少。因此，该项目的目的是确定涉及蛋白激酶和磷酸酶在心脏中A1R-，A2AR和A3R介导的作用中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方面的运行。使用RAT和A1 R，A2AR和Double（A1R+A2AR）敲除型小鼠心室心肌细胞，心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 s osoforms cosoforms cromotate and croppation and crock and croppation and crock（受体激活C Kinase）蛋白质蛋白质肌酸肌酸盐蛋白。还将研究p38-MAPK（有丝分裂原激活的蛋白激酶）参与A1 r介导的抗氧化抗氧化抗氧化抗氧化抗氧化，2）2）2）抗氧化抗抑制作用引起的抗氧化作用的重要性以及PKC同工型是否涉及的抗氧化抗溶液，3）A2AR是否涉及A2AR抗体均具有a2AR的作用。 A1R，A2AR和A3R刺激产生的心脏作用中的磷酸酶，以及5）心肌缺氧和/或缺血如何改变A1 R，A2AR和/或A3R的功能，从而增加或减少其在调节心脏功能中的作用。从这些研究中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，这些发现应显着有助于我们对正常和患病心脏中G蛋白偶联受体手术的分子机制的了解。此类信息应该对开发新疗法和药物的开发有助于减轻心脏功能障碍。