PURINERGIC SIGNALING IN CULTURED HEART CELLS

描述(研究人员摘要)：腺苷受体的激活 对心脏有重要影响。功能组件的存在 心脏细胞上的腺苷A3受体提示一种新的心脏功能 这种感受器。以培养的心脏房室细胞为研究对象 关于模型，本提案的总体目标是调查 腺苷A3受体的信号机制、调节和功能 并研究A1和A3受体的作用及其潜在的 心肌细胞预适应的机制。具体地说， 提案将1)对心脏进行药理学表征 A3受体，2)研究潜在的效应分子，如磷脂酶， A3受体偶联的腺酰环化酶和KATP通道，以及 3)研究A3受体偶联效应的脱敏作用。因为 A1和A3受体可能具有不同的信号机制和功能 并可通过腺苷激动剂表现出不同的脱敏作用 对A1受体的研究将用于直接比较。使用 一种新的心肌细胞预适应模型，建议 将进一步研究A1和A3受体在启动 和调节预适应的保护作用，以及5)研究 激活每个受体诱导预适应和 确定蛋白激酶C和KATP通道在此过程中的作用 保护现象。此外，心房肌细胞只表达A1 预适应的受体和表现特征类似于 A1受体介导的心肌预适应的特点 肌细胞。因此，心房肌细胞代表了一种有用的“零”心肌细胞模型 A3受体及转导A3受体基因的心房肌细胞 用来进一步检测A3受体的功能和信号机制 在预适应过程中。这项建议应该产生重要的和新的 腺苷和腺苷的心脏作用和信号机制的研究进展 其受体亚型。

DESCRIPTION (Investigator's Abstract): Activation of adenosine receptors exerts important effects in the heart. The presence of a functional adenosine A3 receptor on the heart cell suggests a novel cardiac function for this receptor. Using cultured cardiac atrial and ventricular cells as models, the overall objective of the present proposal is to investigate the signaling mechanism, regulation, and function of the adenosine A3 receptor and to investigate the role of A1 and A3 receptors and the underlying mechanisms in preconditioning of cardiac myocytes. Specifically, the proposal will 1) carry out pharmacological characterization of the cardiac A3 receptor, 2) investigate the potential effectors, such as phospholipases, adenylyl cyclase and KATP channel, to which the A3 receptor is coupled, and 3) characterize desensitization of A3 receptor-coupled effectors. Because A1 and A3 receptors may have different signaling mechanisms and functions and may exhibit differential desensitization by adenosine agonist, parallel studies on the A1 receptor will be performed for direct comparison. Using a novel cardiac ventricular myocyte model of preconditioning, the proposal will further 4) investigate the role of A1 and A3 receptors in initiating and mediating the protective effect of preconditioning, and 5) study the mechanism by which activation of each receptor induces preconditioning and determine the role of protein kinase C and KATP channel in mediating this protective phenomenon. Moreover, atrial myocytes express only the A1 receptor and exhibit characteristics of preconditioning similar to the characteristics of A1 receptor-mediated preconditioning in the ventricular myocytes. Thus, atrial myocytes represent a useful "null" myocyte model for the A3 receptor and atrial myocytes transfected with A3 receptor cDNA will be used to further test the function and signaling mechanism of A3 receptor during preconditioning. The proposal should yield important and new information on the cardiac actions and signaling mechanisms of adenosine and its receptor subtypes.