PHARMACOLOGY OF CARDIAC A ADENOSINE RECEPTORS

拟议的研究的主要目标是阐明分子 和生化机制参与了信息的传递 腺苷与膜结合A1受体的相互作用 心血管功能的改变。腺苷从细胞中释放出来 在正常和病理情况下，如缺血和 与A1受体相互作用直接抑制腺苷环化酶活性， 钝儿茶酚胺的作用，诱发心动过缓和房室结 阻断，抑制脂肪分解，诱导镇静。最近的证据 提示A1受体与离子等其他效应系统偶联 通道(钙和钾)和直接对磷酸二酯酶。这一机制 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 为了使A1受体表征其结构(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 病理条件下其结构的变化；2)纯化A1 腺苷受体用多种层析技术进行探查 它的结构，以及它如何与其他成分(N蛋白)相互作用 系统和提高抗体的受体；3)利用细胞 用含A1受体的培养模型研究细胞周期调控 CAMP依赖和非依赖的受体-效应偶联 机械装置。该细胞模型还将用于研究人的细胞生物学。 A1受体的合成和膜循环。终极目标 这项拟议的研究的目的是了解A1受体系统如何 对健康和疾病都有作用，所以我们可以操纵它的 用于治疗益处的成分。例如，腺苷的作用 通过A1受体的作用在心肌细胞中可能很重要 心肌梗死(房室结传导阻滞和收缩抑制)和腺苷和 它的类似物在治疗室上性心律失常方面很有用。

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.