DI, S.; MALCHER LOPES, R.; TASKER, J.G.; Tulane University; Tulane University; Tulane University: Novel steroid modulation of hypothalamic neuroendocrine cells
Adrenal corticosteroids have both fast and slow feedback effects on pituitary hormone release via actions in the hypothalamus. Using whole-cell patch clamp electrophysiology in hypothalamic slices, we have studied the acute effects of glucocorticoids on the electrical activity of identified neuroendocrine cells of the hypothalamic paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the rat. The glucocorticoids dexamethasone and corticosterone caused a dose-dependent, steroid-specific suppression of the release of glutamate and an enhancement of GABA release onto identified subpopulations of PVN and SON neuroendocrine cells within 3-5 min, suggesting a non-transcriptional inhibitory effect of the steroids on presynaptic glutamate afferents and facilitatory effect on GABA afferents. These effects are not blocked by conjugating the steroid to membrane-impermeant albumin, or by prior application of the type I and II corticosteroid receptor antagonists spironolactone and RU486, implicating a non-conventional membrane corticosteroid receptor with differing actions on glutamate and GABA release mechanisms. Surprisingly, the glucocorticoid effects are abolished by blocking postsynaptic G protein activity, suggesting that the receptor is located on the postsynaptic neuroendocrine cell membrane, and that it triggers the release of one or more retrograde messengers by activating a G protein signaling cascade. Both the glucocorticoid suppression of glutamate release and facilitation of GABA release are blocked completely by type I cannabinoid receptor (CB1) antagonists, and the suppression of glutamate release is mimicked with CB1 agonists, implicating endocannabinoids as the associated retrograde messenger(s). These data indicate a novel membrane glucocorticoid receptor that is coupled to endocannabinoid synthesis and release via a G protein-dependent signaling mechanism. Supported by NIH MH066958.
