Annexin 1: a paracrine/juxtacrine mediator of glucorticoid action in the neuroendocrine system

Abstract

Glucocorticoids (GCs) play an essential role in the maintenance of homeostasis. In normal circumstances their secretion is tightly regulated by a complex servo mechanism through which the steroids suppress the synthesis and release of ACTH and its hypothalamic releasing factors (CRH and AVP) and thereby reduce the positive drive to the adrenal cortex. The feedback actions of GCs on hormone release develop rapidly (within minutes), well before any changes in hormone synthesis are apparent. By using immunoneutralization, gene targeting and pharmacological strategies in in vivo and in vitro models, we have identified annexin 1, a Ca 2þ -and phospholipid-binding protein, as a key mediator of the early inhibitory actions of GCs on peptide release. This brief review outlines this work and describes molecular and cellular studies which have provided insight into the mechanism of annexin 1-dependent GC signalling in the neuroendocrine system.

Rapid Glucocorticoid Receptor-Mediated Inhibition of Hypothalamic–Pituitary–Adrenal Ultradian Activity in Healthy Males

“…At the level of the pituitary in vitro, however, rapid inhibition of membrane potential (Hua and Chen, 1989) and ACTH release (Dayanithi and Antoni, 1989;John et al, 2002;Buckingham et al, 2003) occurs via a nongenomic Annexin 1-mediated GR mechanism (Taylor et al, 1993). Our data reveal a response that is more rapid than demonstrated for Annexin 1 and fits better with recent in vitro and in vivo evidence for rapid corticosteroid processes acting via a membrane-bound GR (Tait et al, 2008;Breuner and Orchinik, 2009;Roy and Rai, 2009), probably mediated through a phosphatidylinositol 3-kinase pathway (Limbourg et al, 2002;Matthews et al, 2008;Roy and Rai, 2009).…”

Mechanisms of rapid glucocorticoid feedback inhibition of the hypothalamic–pituitary–adrenal axis

“…While it is likely that the rapid glucocorticoid actions are mediated by membrane-associated corticosteroid receptors in each of the potential targets of fast feedback, the receptors responsible for, and the cellular mechanisms of the rapid corticosteroid inhibitory actions appear to differ in the various target structures. Although rapid corticosteroid actions in the hypothalamus appear to be mediated largely by glucocorticoid-induced endocannabinoid regulation of excitatory synaptic inputs to PVN neuroendocrine cells, the rapid corticosteroid modulation of synaptic excitation is independent of endocannabinoid production in the hippocampus (Olijslagers et al 2008), is mediated by a combination of endocannabinoid-dependent and endocannabinoid-independent mechanisms in the BLA (Karst et al 2010), and is clearly not mediated by synaptic modulatory mechanisms in the anterior pituitary (Buckingham et al 2003). The challenge going forward will be to assign these rapid corticosteroid effects to feedback vs. feedforward physiological functions and to integrate the diverse rapid signals into a coordinated feedback regulation of the HPA axis.…”

What Can We Learn about Autism from Studying Fragile X Syndrome?

“…We have reported a higher frequency of acetylation of the glucocorticoid-negative regulator annexin-1 in males with FXS than in normal controls [87], particularly in those with severe social withdrawal [88]. Since annexin-1 is involved in the acute phase of cortisol modulation [89], it is unclear whether our finding is related to the abnormal response to cognitive and social challenges (late phase) [85]. Another candidate for abnormal cortisol regulation in FXS is the glucocorticoid receptor alpha.…”