es, the hypothalamus releases corticotropin-releasing hormone (CRH) whose signaling results in activation of protein kinase A (PKA) pathway and the expression and release of pro-opiomelanocortin (POMC) gene from the pituitary. Processing of POMC gives rise to several peptides of which adrenocorticotropin (ACTH), specifically binding to melanocortin receptor type 2 (Mc2r) also setting in motion PKA, prompts the expression of steroidogenic genes and the secretion of cortisol from the adrenal cortex. Cortisol binds the glucocorticoid receptor Nr3c1, a nuclear hormone receptor. In the absence of ligand Nr3c1 is predominantly cytoplasmic and dynamically complexed with a chaperone/co-chaperone machinery that is critical for its function and turnover. Like the other members of the nuclear receptor superfamily, Nr3c1 is modular consisting of trans-activation, DNA-binding (DBD) and ligand-binding (LBD) domains. The N-terminal trans-activation domain 1 (AF-1) is ligand independent whereas a second domain (AF-2), embedded in the LBD, is ligand dependent. The DBD, which contains two zinc fingers motifs, is the most conserved domain within the family. Two main receptor isoforms are generated through alternative splicing of which the alpha represents the classic glucocorticoid receptor. The beta isoform, thought to be largely disordered, does not bind glucocorticoids and while residing in the nucleus does not regulate gene expression. Yet, if co-expressed with the alpha isoform, it can act as an inhibitor of the classic receptor, suggesting a possible modulator role. Additional splice and translational isoforms have been reported. Upon ligand binding, Nr3c1 translocates to the nucleus where it binds as a homodimer to specific glucocorticoids response elements (GRE) or, possibly as a monomer, to other transcription factors to enhance or downregulate the transcription of many genes. The receptor may bind negative GRE as another mechanism of repression. In addition, Nr3c1 interacts with many coactivators and corepressors that modulate the outcomes of its function. Nr3c1is a substrate for many post-translational modifications that affect in various ways its function and fate. The receptor plays important roles in the negative feedback loop the pathway provides for the upstream components of the HPA axis. A notable example is the repression of POMC gene expression. While POMC, and also CRH genes appear to harbor negative GREs, Nr3c1 has been reported to bind to and antagonize the function of Nr4a1, an orphan nuclear receptor and transcriptional mediator of POMC expression. The Nr3c1 coactivator Brg1 is crucial for the interaction; the complex can then recruit Hdac2 and silence gene expression. Glucocorticoid deficiency or excess has been associated with several pathophysiological conditions. To see the ontology report for annotations, GViewer and downloads, click here...(less)