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CYCUC AMP AS AN INTRACELLULAR MEDIATOR OF HORMONE ACTION: SUTHERLAND'S CRITERIA REVISITED IRA WEINRYB* Since the demonstration in 1956 by the late Earl W. Sutherland and his colleagues that a heat-stable, dialyzable factor [1], later identified as adenosine 3',5' cyclic monophosphate (cyclic AMP), [2], mediated the glycogenolytic effects of glucagon, investigations of the significance of this cyclic nucleotide in physiologic processes have numbered in the thousands. Cyclic AMP has been implicated as an intracellular messenger in a host of diverse areas, including central nervous system function [3], the immune response [4], and cellular growth and differentiation [5]. Recent years have brought a critical reexamination of the roles of cyclic AMP, particularly in mammalian physiology. Investigators are reporting , in increasing numbers, data that form the bases for doubt about the importance of cyclic AMP in several areas, such as the stimulation of cardiac inotropism by /3-adrenergic agonists [6], the modulation of smooth muscle tone by vasoactive agents [7], the initiation of lymphocyte transformation by mitogen or antigen [5], and the maturation of prethymocytes under the influence of thymic hormones [8]. Why has skepticism replaced euphoria? In part the present difficulties may stem from an apparent failure to satisfy a number ofcriteria for the mediation by cyclic AMP of a hormone or hormone-like effect on a tissue or cell. These were perhaps first described in a review article by Sutherland and Robison, published in 1966 [9]. A proper discussion of Sutherland's criteria (as they have come to be known) requires a short description of the generally accepted ideas about the metabolism of cyclic AMP upon presentation of a hormone to its target cell. The binding of a hormone to its specific receptor on the ?Department of Biochemistry and Drug Disposition, USV Pharmaceutical Corporation, Tuckahoe, New York 10707. 1 wish to thank Drs. Richard G. Van Inwegen and Charles A. Sutherland for their critical evaluation of this manuscript.© 1979 by The University of Chicago. 0031-5982/79/2203-0071$01.00 Perspectives in Biology and Medicine · Spring 1979 | 415 external surface of the plasma membrane of a target cell leads to changes in the membrane. These perturbations stimulate the adenylate cyclase enzyme which is associated with the internal surface of the plasma membrane. Adenylate cyclase catalyzes the formation of cyclic AMP from intracellular ATP. The cyclic AMP so formed can be hydrolyzed by specific cyclic nucleotide phosphodiesterases (PDEs) to 5' AMP, which would have little if any biological activity in a cyclic AMPspecific process, thus "turning off" the hormonal message. The effects ofcyclic AMP within the cell are thought in almost all cases to be a result of stimulation of a family of cyclic AMP-dependent protein kinases. These enzymes phosphorylate a variety of eellular proteins and enzymes , leading in one or more additional steps to the physiologic response appropriate to the hormone and the target tissue. The cyclase, PDE, and kinase are modulated by multiple cellular components, both low-molecular-weight and macromolecular, as might be expected for an important intracellular messenger, but the details of these actions need not concern us here. Sutherland's criteria address several key aspects of this scheme. In essential paraphrase, they are as follows [9]: 1 . Does the hormone in question stimulate adenylate cyclase in broken cell preparations from the target tissue? 2.Does addition of hormone to intact cells cause a change in cyclic AMP concentration rapid enough to precede or coincide with the physiologic response? 3.Can the hormonal effect be mimicked by cyclic AMP or a cyclic AMP analog? If so, can the hormonal effect be potentiated by methylxanthines ? If not, is there a satisfactory explanation? With the benefit ofhindsight, three comments are worth making here. First, these criteria do not recognize the role of the kinases in the elaboration of the physiologic effect—understandable since the ubiquity of the kinases was not yet appreciated. Second, potentiation by the methylxanthines refers to the ability of PDE inhibitors (at that time, caffeine and theophylline) to enhance the effect of a hormone by protection of the nascent cyclic nucleotide from degradation. Theophylline, in particular , has turned out to be a poor choice as a PDE inhibitor, for reasons we...

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Additional Information

ISSN
1529-8795
Print ISSN
0031-5982
Pages
pp. 415-420
Launched on MUSE
2015-01-07
Open Access
No
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