Nontranscriptional actions of the glucocorticoid receptor

Abstract

Many cellular responses to corticosteroids involve the transcriptional modulation of target genes by a prototypical nuclear receptor, the glucocorticoid receptor (GR). In the classic model of steroid hormone action GR acts as ligand-dependent transcription factor by either activating or repressing gene expression through direct interactions with DNA or other transcription factors. Recent evidence suggests an important role for nontranscriptional effects of GR in the vascular system. The nontranscriptional actions of GR involve the rapid activation of protein kinases, such as phosphatidylinositol-3 kinase and Akt, leading to the activation of endothelial nitric oxide synthase. This novel pathway of steroid hormone action protects against ischemic injury by augmenting blood flow and decreasing vascular inflammation.

Fig. 1

GR activates Akt through PI3 K. Above Effect of Dex with and without RU486 (RU) and LY294002 (LY) on Akt kinase activity, measured by phosphorylation of the Akt downstream target GSK-3 by immunoblotting (P-GSK-3). Below Immunoblotting for total Akt levels in the kinase reaction. (Reprinted from [9])

Fig. 2

Nuclear and nonnuclear actions of the glucocorticoid receptor. Association of GR with the regulatory p85 subunit of PI3 K stimulates formation of 3′-phosphorylated phosphatidylinositols (e.g., phosphatidylinositol 3,4,5-trisphosphate, PIP₃) from phosphatidylinositol phosphate precursors (e.g., phosphatidylinositol 4,5-trisphosphate, PIP₂). This leads to the subsequent recruitment and activation of protein kinase Akt, which enhances NO release through phosphorylation of eNOS. In the nucleus GR binds either directly to glucocorticoid response elements (GRE) or modulates the function of other transcription factors