When agonists bind to beta-adrenergic receptors on intact cells, adenylate cyclase is activated and cyclic adenosine monophophate (cAMP) accumulates within the cells. Within several minutes, however, this response is blunted, and the receptor-mediated response is said to be """"""""desensitized"""""""". Studies of desensitization have focussed on the interaction between agonists and receptors. It has been clearly established in many experimental systems that the interaction of an agonist with beta-adrenergic receptors involves far more than just reversible binding. Following initial binding of the agonist, the affinity of the receptor for that agonist may change, the receptor may move from the cell surface to intracellular sites, the receptor becomes functionally uncoupled from the nucleotide binding protein that couples the receptors to adenylate cyclase, and the number of receptors may decrease. The relationships of these events to each other and to desensitization are still unclear. Human mononuclear leukocytes have beta-adrenergic receptors linked to a stimulation of adenylate cyclase, and desensitization of these receptors has been demonstrated in vivo and in vitro. Studies of these receptors are important because they allow direct assessment of beta adrenergic receptors in people. Furthermore, it is important to study normal, healthy mammalian cells.
The aim of this grant is to study in vitro desensitization of the beta adrenergic receptors in human mononuclear leukocytes, and to examine various mechanisms that may account for desensitization using both new and old techniques. Other experiments will ask a related question: Do agonists get internalized with receptors and do the agonists get metabolized? Finally I will examine how corticosteroids alter desensitization. Desensitization is a widespread mechanism by which the responsiveness of cells to hormones and neurotransmitters is regulated. Beta-adrenergic receptors are present in many organ systems and play a key role in cardiovascular physiology. Furthermore, agonists and antagonists directed at these receptors are among the most widely used drugs in cardiovascular pharmacology. The studies proposed here ask fundamental questions about the regulation of receptors in normal human cells, and offer the potential of developing new tools for use in clinical studies.
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