PHARMACOLOGY OF CARDIAC A ADENOSINE RECEPTORS

拟议研究的主要目标是阐明 和生物化学机制参与的信息转导， 腺苷与膜结合A1受体的相互作用， 心血管功能的改变。 细胞释放腺苷 在正常和病理条件下如局部缺血， 与A1受体相互作用以直接抑制腺苷酸环化酶活性， 减弱儿茶酚胺的作用，诱导心动过缓和房室结 阻滞，抑制脂肪分解和诱导镇静。 最近的证据 表明A1受体与其他效应子系统如离子 通道（Ca++和K+）和磷酸二酯酶直接。 机制 A1受体与生理效应的偶联在很大程度上仍然存在 未知 这些研究将：1）开发和利用光亲和配体 对于A1受体，以表征其结构（蛋白质和糖蛋白 特征）在包括心脏在内的各种组织中，并研究 在病理条件下改变其结构; 2）纯化A1 腺苷受体，使用各种色谱技术来探测 它的结构，以及它如何与其他成分（N蛋白）相互作用， 系统并产生针对受体的抗体; 3）利用细胞 含有A1受体的培养模型，以研究 cAMP依赖性和非依赖性的受体-效应器偶联 机制等 该细胞模型还将用于研究 A1受体的合成和膜循环。 最终目标 研究的目的是了解A1受体系统 在健康和疾病中发挥作用， 成分的治疗益处。 例如，腺苷的作用 通过A1受体起作用可能在心肌细胞中很重要， 梗死（房室结传导阻滞和收缩性降低）和腺苷， 其类似物可用于治疗室上性心律失常。

The major goal of the proposed research is the elucidation of the molecular and biochemical mechanisms involved in the transduction of information from the interaction of adenosine with membrane bound A1 receptors to alterations in cardiovascular function. Adenosine is released from cells under both normal and pathologic conditions such as ischemia and can interact with A1 receptors to directly inhibit adenylate cyclase activity, to blunt the effects of catecholamines, to induce bradycardia and AV nodal block, to inhibit lipolysis and to induce sedation. Recent evidence suggests A1 receptors are coupled to other effectors systems such as ion channels (Ca++ and K+) and to phosphodiesterases directly. The mechanism of coupling of A1 receptors to physiologic effects remains largely unknown. These studies will: 1) develop and utilize photoaffinity ligands for the A1 receptor to characterize its structure (protein and glycoprotein characteristics) in a variety of tissues including the heart, and to study alterations in its structure under pathologic conditions; 2) purify the A1 adenosine receptor using a variety of chromatographic techniques to probe its structure, and how it interacts with other components (N protein) of the system and to raise antibodies against the receptor; 3) utilize cell culture models containing A1 receptors to study regulation of receptor-effector coupling for both cAMP-dependent and independent mechanisms. The cell model will also be used to study the cell biology of the synthesis and membrane cycling of the A1 receptor. The ultimate goal of the proposed research, is to understand how the A1 receptor system functions in both health and disease so that we can manipulate its components for therapeutic benefit. For example, the effects of adenosine acting through the A1 receptor are likely important in myocardial infarction (AV nodal block and depressed contractility) and adenosine and its analogs are useful in the treatment of supraventricular arrhythmias.