Cardiac function is controlled by neurotransmitters, neuromodulators and drugs which bind to specific receptors located in the cardiac membrane. These receptors interact with various effector mechanisms to regulate cellular activity. The long term goal of this project is to elucidate the biochemical mechanisms involved in the regulation of receptor function and receptor; effector coupling in the heart. The present proposal addresses specific questions related to muscarinic cholinergic and adenosine receptors. There are two specific aims: 1) We will determine how and if the cardiac muscarinic receptor is regulated by receptor phosphorylation. The molecular events associated with the recently demonstrated process of agonist-mediated receptor phosphorylation will be elucidated. The protein kinase(s) which phosphorylate the receptor in the intact call will be identified. Other studies will be targeted to determine the consequences on receptor phosphorylation of receptor function. The effects of receptor phosphorylation on the ability of the receptor to bind ligands and interact with G-proteins will be characterized. The possible role of phosphorylation in receptor desensitization will be determined. 2) The cardiac adenosine receptor system will be thoroughly analyzed in terms of biochemical aspects of receptor properties as well as receptor: effector mechanisms. The nature of the cardiac adenosine receptor:effector mechanism(s) will be thoroughly analyzed and compared to the effector mechanisms used by cardiac muscarinic receptors. Other studies will determine if different subpopulations of cardiac adenosine receptors exist, and if they are linked to different effectors. It is anticipated that the results obtained will provide fundamental insights into the biochemical events involved in the processes of receptor regulation and receptor:effector coupling in the heart.
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