The Search for the Mechanism of Hormone Action

THE SEARCH FOR THE MECHANISM OF HORMONE ACTION J. R. TATA* The enormous interest generated in studying hormone action can be gauged from the vast literature and multitude of national and international conferences and workshops currently devoted to this subject. It is also an area of biomedical research that depends heavily on close interaction among different scientific disciplines and one in which international collaboration has much to offer. Some fundamental principles of cellular regulation have emerged from work designed to unravel the mechanism of action of hormones. For example, the discovery ofcyclic AMP and the subsequent realization of the importance of protein phosphorylation in every possible biological regulatory process stem directly from Sutherland's efforts to elucidate how epinephrine (adrenaline) and glucagon control glycogen metabolism [I].1 The discovery of the importance of movement of calcium into and out of cells in numerous cellular and physiological functions also owes its origins to investigations of hormonal control of calcium distribution, work carried outjointly in laboratories in the United States, England, France, and Japan [2]. Similarly, some of our present knowledge about the organization and transcription of eukaryotic genes can be attributed to discovery of how steroid hormones control gene activity, particularly where it concerns the expression of genes coding for egg proteins [3, 4]. Here too, collaboration among scientists in the United States and Europe is responsible for the rapid advance in our understanding of hormonal control of gene expression. In the course of these advances a commonly held view has arisen that there is something inherently unique about how hormones act. In this *Head, Laboratory of Developmental Biochemistry, National Institute for Medical Research , Mill Hill, London NW7 IAA, United Kingdom. 'This area of research benefited enormously from the first international conference on cyclic AMP sponsored by the Fogarty Center, which brought together scientists of different disciplines from all over the world.© 1986 by The University of Chicago. All rights reserved. 0031-5982/86/2932/$0 1.00 S 184 [J. R. Tata ¦ Mechanism ofHormone Action review I shall examine the validity of such a tenet by considering historical , evolutionary, and phenomenological observations relevant to hormone action. I shall argue that, whereas it is important to study hormone action as part ofa general molecular and cellular approach to regulatory mechanisms, common mechanisms of hormonal regulation do not exist. It is therefore futile to search for principles uniquely applicable to hormone action; rather, it would be more profitable to exploit hormones as tools to explore general principles of biological regulation. Important Characteristics ofHormones Hormones have been defined in several different ways [5]. The simplest , and therefore the most flexible, definition is that these are substances usually produced in response to an environmental demand by one group of cells in a multicellular organism to regulate the activity of another group. It is worth noting the following important features of hormones in the context of their mechanism of action: (1) Hormones do not represent a special class of substances. They comprise chemicals varying from simple two-carbon compounds to small peptides, large polypeptides, steroids, phenols, terpenoids, fatty acid derivatives, catecholamines , and so on. (2) The same hormone may exert quite different actions in different tissues of the same organism, or in the same tissue of different organisms. For example, thyroid hormones and ecdysteroids exert totally different actions in the different tissues of the premetamorphic larvae of amphibia and insects. (3) Conversely, different hormones may regulate the same function in different target cells of the same organism, an example being the regulation of a-amylase activity in the mouse salivary gland and pancreas by testosterone and insulin, respectively . (4) Many physiological or complex biochemical functions, such as lactation, glycogenolysis, sugar transport, etc., are regulated by the combined action of different hormones. (5) One hormone may modulate the action of another. For example, estrogen is known to alter the response of uterine and oviductal cells to progesterone. Past and Present Concepts ofHormone Action Early ideas on unified hypotheses to account for the action of all, or large groups of, hormones were based on complex metabolic functions at the tissue level, such as respiration, glycolysis, etc. The increasing availability of purified enzymes in the 1930s and 1940s...