PURINERGIC SIGNALING IN CULTURED HEART CELLS

描述（研究者摘要）：腺苷受体激活 对心脏有重要影响。 存在功能性 心脏细胞上的腺苷A3受体提示新的心脏功能 对于这个受体。 利用培养的心房和心室细胞作为 模型，本提案的总体目标是调查 腺苷A3受体的信号传导机制、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。 具体而言是 建议将1）进行心脏的药理学表征 A3受体，2）研究潜在的效应物，如磷脂酶， 腺苷酸环化酶和KATP通道，A3受体与之偶联，和 3)表征A3受体偶联效应物的脱敏。 因为 A1和A3受体可能具有不同的信号传导机制和功能 并且可能表现出腺苷激动剂的差异脱敏， 将对A1受体进行研究，以进行直接比较。 使用 一种新的心肌细胞预适应模型， 将进一步4）研究A1和A3受体在启动 并介导预处理的保护作用; 5）研究 每种受体的激活诱导预适应的机制， 确定蛋白激酶C和KATP通道在介导这一过程中的作用。 保护现象。 此外，心房肌细胞仅表达A1 受体，并表现出类似的预处理的特点， A1受体介导的心室肌预适应的特点 肌细胞 因此，心房肌细胞代表了一个有用的“空”肌细胞模型， A3受体和用A3受体cDNA转染的心房肌细胞将 用于进一步检测A3受体的功能和信号转导机制 在预处理期间。 该提案应产生重要的和新的 关于腺苷的心脏作用和信号机制的信息， 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.