Minireview: rapid glucocorticoid signaling via membrane-associated receptors

Abstract

Glucocorticoids are secreted into the systemic circulation from the adrenal cortex and initiate a broad range of actions throughout the organism that regulate the function of multiple organ systems, including the liver, muscle, the immune system, the pancreas, fat tissue, and the brain. Delayed glucocorticoid effects are mediated by classical steroid mechanisms involving transcriptional regulation. Relatively rapid effects of glucocorticoids also occur that are incompatible with genomic regulation and invoke a noncanonical mode of steroid action. Studies conducted in several labs and on different species suggest that the rapid effects of glucocorticoids are mediated by the activation of one or more membrane-associated receptors. Here, we provide a brief review focused on multiple lines of evidence suggesting that rapid glucocorticoid actions are triggered by, or at least dependent on, membrane-associated G protein-coupled receptors and activation of downstream signaling cascades. We also discuss the possibility that membrane-initiated actions of glucocorticoids may provide an additional mechanism for the regulation of gene transcription.

FIG. 1

Rapid glucocorticoid feedback inhibition of the HPA axis. Glucocorticoids (CORT) are secreted into the blood from the adrenal glands in response to stress activation of the HPA axis, and the circulating glucocorticoids feed back to the anterior lobe of the pituitary gland, the hypothalamic PVN, and the hippocampus (not shown). Glucocorticoids inhibit CRH neuron activity via endocannabinoid release in the PVN and curtail HPA hormone release within minutes of reaching the PVN.

FIG. 2

Model of rapid glucocorticoid signaling in PVN parvocellular neuroendocrine cells. A, Glucocorticoids (CORT) bind to a membrane-associated receptor (mbGR) and activate a G protein-dependent intracellular signaling pathway that leads to endocannabinoid (CB) synthesis and retrograde release. Endocannabinoids bind to presynaptic CB1 cannabinoid receptors and suppress glutamate release from glutamate synapses onto the PVN neuron. B, Proposed membrane glucocorticoid receptor signaling pathway. In this model, the membrane glucocorticoid receptor (mbGR) is a stimulatory G protein-coupled receptor (Gs) that, upon binding corticosterone (CORT), triggers the activation of adenylyl cyclase and the production of cAMP, resulting in increased PKA activity, which leads downstream to endocannabinoid synthesis from membrane lipid precursors followed by release.