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.
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