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Jeffrey Tasker"Rapid glucocorticoid modulation of hypothalamic neuroendocrine cells via a novel membrane receptor"

Abstract :

Glucocorticoid negative feedback in the brain during stress regulates the stress response, feeding, reproduction and neural-immune interactions, in part, by modulating neuroendocrine function.
This feedback inhibition is both acute, by rapidly suppressing peptide secretion, and sustained, by reducing peptide expression. We recently found that glucocorticoids cause a rapid, non-genomic suppression of excitatory glutamatergic synaptic inputs to both parvocellular and magnocellular neurons of the hypothalamic paraventricular nucleus (PVN) and supraoptic nucleus (SON). This rapid glucocorticoid modulation is mediated by the activation of a putative membrane G protein-coupled glucocorticoid receptor, which leads to the retrograde release of the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Leptin, an anorexigenic peptide secreted by adipose tissue, was shown to inhibit fasting-induced endocannabinoid synthesis in the hypothalamus, suggesting a possible interaction between leptin receptor and membrane glucocorticoid receptor signaling mechanisms. We found that the glucocorticoid-induced, endocannabinoid-mediated suppression of glutamate release onto hypothalamic neurons is blocked by leptin, and that the leptin effect is mediated by the activation of phosphodiesterase 3B, implicating a cAMP signaling mechanism in the rapid glucocorticoid effect. Indeed, we then showed that the glucocorticoid-induced endocannabinoid effect was dependent on activation of a Gs-cAMP-PKA signaling pathway. Interestingly, glucocorticoids also caused a rapid faciltitation of GABA release onto magnocellular, but not parvocellular, neurons of the PVN, and this effect was also dependent on a retrograde messenger, but it was not mediated by endocannabinoid release and it was not blocked by leptin, implicating a separate glucocorticoid receptor signaling pathway leading to the release of a second retrograde messenger. The rapid glucocorticoid effects on both glutamate and GABA release were blocked by both naloxone and a selective orphanin FQ receptor antagonist, suggesting that the putative membrane glucocorticoid receptor is an orphanin FQ-like receptor. The rapid glucocorticoid effects, therefore, are mediated by the activation of a novel, G protein-coupled glucocorticoid receptor and may play a key role in the acute regulatory effects of stress-induced corticosteroid secretion on neuroendocrine function.

Selected publications

Tasker JG. Linkscocorticoid actions in the hypothalamus as a mechanism of homeostatic integration.Obesity (Silver Spring). 2006 Aug;14 Suppl 5:259S-265S. Review.

Tasker JG, Di S, Malcher-Lopes R.
Minireview: rapid glucocorticoid signaling via membrane-associated receptors.
Endocrinology. 2006 Dec;147(12):5549-56. Epub 2006 Aug 31.

Malcher-Lopes R, Di S, Marcheselli VS, Weng FJ, Stuart CT, Bazan NG, Tasker JG.
Opposing crosstalk between leptin and glucocorticoids rapidly modulates synaptic excitation via endocannabinoid release.
J Neurosci. 2006 Jun 14;26(24):6643-50.

Aude Panatier