Journal of Neuroendocrinology, 1996, Vol. 8, 659–672 Mortyn Jones Memorial Lecture — 1995 Calcium Checks cyclic AMP — Corticosteroid Feedback in Adenohypophysial Corticotrophs Ferenc A. Antoni Medical Research Council Brain Metabolism Unit, Department of Pharmacology, University of Edinburgh, Edinburgh, EH8 9JZ, Scotland, UK. Key words: stress response, glucocorticoid, adrenocorticotrophic hormone, corticotrophin releasing-factor, adenylyl cyclase, membrane potential, calcium-activated potassium currents, calcium binding proteins. Abstract This paper summarizes a par ticular aspect of the stress response — the negative feedback control of anterior pituitary adrenocor ticotrophin secretion with special focus on the mechanism of action of protein(s) rapidly induced by glucocorticoids. The main thesis is that the principal intracellular mechanism underlying cor ticosteroid inhibition of corticotroph secretor y function is the opposition of cAMP-mediated activation by calcium ions. An increase of intracellular cAMP levels in cor ticotrophs produces a rise in intracellular free Ca2+ known to be essential for triggering hormone secretion. In parallel, calcium regulates agonist-induced cAMP accumulation through inhibition of adenylyl cyclase and the stimulation of cAMP-degrading phosphodiesterase. Furthermore, a key action of cAMP is the inhibition of a slow, sustained potassium current which is activated by calcium ions. Collectively, the actions of calcium constitute a powerful intracellular feedback inhibition of cAMP-induced cellular activation. Analysis of cor ticosteroid action in mouse corticotroph tumour (AtT20) cells indicates that the essence of corticosteroid feedback inhibition is the amplification of intracellular calcium feedback. A common mediator of the inhibitory actions of calcium may be the calcium receptor protein calmodulin the de novo synthesis of which is rapidly stimulated by glucocorticoid hormones. Targets of glucocorticoid-induced calmodulin may include the protein phosphatase calcineurin, calmodulin- activated phosphodiesterase(s), and BK-type potassium channels. The net result of calcium feedback inhibition is a reduction of Ca2+ available for the facilitation of secretory activity i.e. calcium-induced desensitization. It is proposed that the intracellular calcium feedback loop outlined above also operates in the CNS components of negative corticosteroid feedback. A personal note: Professor Mort yn Jones introduced me to this field of research. His open-minded and critical approach to experimental work has always remained a guiding principle for my own efforts, and I hope that this paper which is dedicated to his memory will be found worthy of its purpose. General aspects of the stress response steady-state. Thus optimized, servomechanism-based control of hypothalamic-pituitary-adrenocortical activity during the stress Adrenal corticosteroids are involved in several fundamental response is vital for successful adaptation (5). regulatory processes of the body including, amongst others, neural A further important aspect of regulation by corticosteroids development, salt-water balance and the stress response (1 ). stems from the fact that these hormones are potent controllers of The corticosteroid component of the stress response is thought gene expression in virtually all organs of the body. Relatively to have a generalized inhibitory function ( 2, 3 ), which is to small excursions of plasma corticosteroid levels beyond either terminate several compensatory processes activated by stressors. end of the normal range (‘set point’) can cause marked and only Examples of such compensatory responses include the activation slowly reversible changes in the functions of organ systems such of the immune system by cytokines, the metabolic adaptation as the immune or the central nervous systems that are essential required for coping with physical or mental stress and adjustments for adaptation to the environment. Hence, negative feedback by the cardiovascular system. The global feedback inhibition by control of corticosteroid secretion has also evolved to allow corticosteroids is fundamental for the successful adaptation to physiologically co-ordinated regulation of gene expression (6 ). environmental challenges as there is plenty of evidence showing It appears that various aspects of corticosteroid feedback in that impairment of the corticosteroid response is associated with the hypothalamic-pituitary-adrenocortical ( HPA) system, in par- an increase of mortality rates to infection and various other ticular the regulation of ACTH under resting conditions, which stressors ( 1, 4 ). In turn, if corticosteroid-mediated suppression is too powerful this may similarly thwart the maintenance of features a distinct circadian pattern in most species (6 ), are Correspondence to: F. A. Antoni, MRC Brain Metabolism Unit, Department of Pharmacology, University of Edinburgh, 1 George Sq. Edinburgh, EH8 9JZ, Scotland, UK. e-mail: Fantoni@tattoo.ed.ac.UK © 1996 Blackwell Science Ltd neur890515 01-08-96 16:43:29 Rev 12.11 The Charlesworth Group, Huddersfield 01484 517077