Rapid intra-adrenal feedback regulation of glucocorticoid synthesis.
The hypothalamic-pituitary-adrenal axis is a vital neuroendocrine system that regulates the secretion of glucocorticoid hormones from the adrenal glands. This system is characterized by a dynamic ultradian hormonal oscillation, and in addition is highly responsive to stressful stimuli. We have recently shown that a primary mechanism generating this ultradian rhythm is a systems-level interaction where adrenocorticotrophin hormone (ACTH) released from the pituitary stimulates the secretion of adrenal glucocorticoids, which in turn feedback at the level of the pituitary to rapidly inhibit ACTH secretion. In this study, we combine experimental physiology and mathematical modelling to investigate intra-adrenal mechanisms regulating glucocorticoid synthesis. Our modelling results suggest that glucocorticoids can inhibit their own synthesis through a very rapid (within minutes), presumably non-genomic, intra-adrenal pathway. We present further evidence for the existence of a short time delay in this intra-adrenal inhibition, and also that at the initiation of each ACTH stimulus, this local feedback mechanism is rapidly antagonized, presumably via activation of the specific ACTH receptor (MC2R) signalling pathway. This mechanism of intra-adrenal inhibition enables the gland to rapidly release glucocorticoids while at the same time preventing uncontrolled release of glucocorticoids in response to large surges in ACTH associated with stress.
College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter EX4 4QF, UK Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Whitson St., Bristol BS1 3NY, UK.
J J
JJ
Walker
Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Whitson St., Bristol BS1 3NY, UK.
F
F
Spiga
College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter EX4 4QF, UK.
R
R
Gupta
Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Whitson St., Bristol BS1 3NY, UK.
Z
Z
Zhao
Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Whitson St., Bristol BS1 3NY, UK.
S L
SL
Lightman
College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter EX4 4QF, UK Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology, University of Bristol, Whitson St., Bristol BS1 3NY, UK j.terry@exeter.ac.uk.
J R
JR
Terry
D000311:Adrenal Glands / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D025461:Feedback, Physiological; D005938:Glucocorticoids / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System; D008297:Male; D008954:Models, Biological; D010913:Pituitary-Adrenal System; D051381:Rats; D017207:Rats, Sprague-Dawley; D044103:Receptor, Melanocortin, Type 2 / Q000378:metabolism; D018043:Receptors, Corticotropin / Q000378:metabolism; D015398:Signal Transduction
D005938:Glucocorticoids; D044103:Receptor, Melanocortin, Type 2; D018043:Receptors, Corticotropin; D000324:Adrenocorticotropic Hormone
adrenal gland; glucocorticoids; hypothalamic–pituitary–adrenal axis; mathematical modelling; stress response