Figure 1. Intracellular circulation and actions of hGRα. hGRα resides in the cytoplasm in the absence of ligand by forming a heterocomplex with several heat shock proteins (HSPs), immunophilins (e.g., FKBP), and some other proteins. Upon binding to ligand cortisol, hGRα dissociates from the complex and translocates into the nucleus through the nuclear pore. Inside the nucleus, hGRα binds directly to glucocorticoid response elements (GREs) located in promoter/enhancer regions of glucocorticoid-responsive genes. DNA-bound hGRα then stimulates transcription rates of glucocorticoid-responsive genes by attracting the regulatory regions the transcription regulatory complex including the RNA polymerase II (RNPII) and its ancillary components through bridging coactivators, such as p300/CBP and p160 proteins. Promoter/enhancer-bound hGRα also recruits in collaboration with these coactivators various chromatin remodeling molecules, including the DRIP/TRAP complex (DRIP/TRAP), the SWI/SNF chromatin modulator (SWI/SNF), and the Mediator complex (MED). In addition to binding directly to DNA and regulating transcription, hGRα interacts indirectly with regulatory regions of glucocorticoid-responsive genes via protein-protein interaction with other transcription factors (TFs) and/or attracted cofactor molecules, ultimately modulating positively and negatively the transcriptional activity of GRE- and non-GRE-containing glucocorticoid-responsive genes. hGRα then moves back to the cytoplasm to re-form a heterocomplex with HSPs for regaining a ligand-friendly status or is cleared from DNA by proteasomal degradation. Further, hGRα can influence the action of cell surface receptors by associating with their intracellular signaling molecules, such as classic and small G-proteins, and several serine/threonine and tyrosine kinases (known as non-genomic actions of glucocorticoids). Accumulating evidence suggests that liganded hGRα also influences the transcription of mitochondrial genes by translocating into this intracellular organelle. CBP: cAMP-responsive element-binding protein (CREB)-binding protein; DRIP/TRAP: vitamin D receptor-interacting protein/thyroid hormone receptor-associated protein complex; FKBPs: FK506-binding proteins; GREs: glucocorticoid response elements; GR: glucocorticoid receptor; HSPs: heat shock proteins; MED: Mediator complex; p160: p160-type nuclear receptor coactivator; RNPII: RNA polymerase II; SWI/SNF: switching/sucrose non-fermenting complex; TFs: transcription factors; TREs: transcription factor response elements.