Stress Hormones: Their Interaction and RegulationJulius Axelrod and Terry D. Reisine

Presentation by Juan-Carlos Andaluz

“The Constancy of the Milieu Interieur is the condition of a free and independent existence” - Claude Bernard

* Harris demonstrated that ACTH release from the pituitary is regulated by corticotropin-releasing factor from the hypothalamus !!* Most scientists thought that CRF was the major, if not the sole means of releasing ACTH from the pituitary

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What did we know about the stress response during the early 20th century? !* Before the early part of the 20th century, Walter Cannon observed that tissues released “sympathin” !* Hans Selye observed a stress syndrome that resulted in the enlargement of the adrenal cortex

!What do we know now?

* CRH release from the hypothalamus (which is essential for stress adaptation and the behavioral and autonomic responses to stress) !!* ACTH release from the pituitary !!* Glucocorticoid release from the adrenal cortex and their inhibitory feedback function (inhibiting CRH & ACTH) !!* Catecholamine synthesis & release !!* Other hormones are involved (VIP, Vasopressing, 3-endorphin, 8-lipotropin, among others)

!What do we know now?

* The stress response involves different parts of the brain that innervate CRH neurons !!*Activation of CRH neurons depends on neural afferents from the brain stem and limbic systems !!* Inhibitory feedback of CRH synthesis & release is mediated by glucocorticoids !!*Induction of CRH transcription is mediated by cAMP/PKA/CREB-dependent pathways

Catecholamine synthesis

* Stress leads to marked compensatory changes in the activity of catecholamine biosynthetic enzymes !!* Changes in the levels & activity of Tyrosine Hydroxylase, Dopa B-Hydroxylase and PNMT are regulated by glucocorticoids, ACTH and neuronal activity !!

Trans-synaptic induction & hormonal regulation of catecholamine synthesis

How do we test whether or not glucocorticoids (subsequently ACTH) & sympathetic nerves modify the formation of epinephrine and norepineprhine?

* Hypophysectomy & Cutting presynaptic nerves (preganglionic innervation to sympathetic nerves)

Plasma norepineprhine levels reflect the activity of the

sympathetic nerves

Epineprhine is a measure of secretion from the adrenal

medulla

If we cut?

If we cut?

Multireceptor Release of ACTH

Maybe Phospholipase

A2?

Desensitization of receptors involved in ACTH release

Desensitization involves:

* Downregulation of CRF receptors !* Decreased density of B-AdreRs !* Uncoupling of receptors from Adenylate cyclase !* Desensitization of each receptor is an independent process and specific to each receptor (e.g. ACTH could still be released in spite of CRF desensitization if VIP or BR stimulate their receptors) !

Inhibition of ACTH Release

Inhibition of ACTH Release by Glucocorticoids

* Reduction of ACTH mRNA activity at some pre translational site !* Inhibition of Phospholipase A2 !* Synthesis of Lipomodulin which inhibits PA2 activity !* At the hypothalamic & pituitary levels, CRH and ATCH gene transcription could be down regulated by negative Glucocorticoid Response elements (GREs) in their promoters !

Possible mechanisms of inhibition:

Glucocorticoids can inhibit gene transcription

Possible molecular mechanism of GR mediated transrepression

* Repression of gene expression could be dependent on GR dimerization !* Although Monomeric GR can still repress CRH & ACTH gene expression by interfering with transcription factors at their promoters (e.g. AP-1, CREB) !

Conclusion: Multihormonal control of ACTH release from the Anterior Pituitary