Calcium Checks cyclic AMP — Corticosteroid Feedback in Adenohypophysial Corticotrophs

Abstract

This paper summarizes a particular aspect of the stress response-the negative feedback control of anterior pituitary adrenocorticotrophin 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 corticosteroid inhibition of corticotroph secretory function is the opposition of cAMP-mediated activation by calcium ions. An increase of intracellular cAMP levels in corticotrophs 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 corticosteroid 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 Mortyn 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.