NR3C1

NR3C1 is the gene that encodes the glucocorticoid receptor (GR), a ligand-activated transcription factor in the nuclear receptor superfamily. The GR mediates many effects of glucocorticoids, such as cortisol, on metabolism, development, and immune function.

Structure and mechanism: The GR protein has an N-terminal activation function domain (AF-1), a central DNA-binding domain with two zinc finger motifs, a hinge region, and a C-terminal ligand-binding domain with activation function AF-2. In the absence of ligand, GR resides in the cytoplasm in a complex with heat shock proteins. Binding of glucocorticoids induces a conformational change, dissociation from chaperones, dimerization, and translocation to the nucleus, where GR binds glucocorticoid response elements (GREs) to regulate gene transcription. GR can activate transcription directly and repress it indirectly, notably by antagonizing NF-κB and AP-1 signaling pathways. Some actions occur through tethering to other transcription factors rather than direct GRE binding.

Isoforms and regulation: In humans, alternative splicing produces GRα, the active receptor, and GRβ, which is unable to bind glucocorticoids and can act as a dominant negative regulator of GRα. GR activity is further modulated by post-translational modifications such as phosphorylation, ubiquitination, and sumoylation, as well as by tissue-specific expression levels.

Physiology and clinical relevance: NR3C1 is widely expressed, with important roles in glucose and protein metabolism, the immune response, and the stress axis. Synthetic glucocorticoids used in medicine, such as dexamethasone, act through NR3C1 and produce anti-inflammatory and immunosuppressive effects. Dysregulation or mutations of NR3C1 can contribute to glucocorticoid resistance, hypersensitivity, Cushing’s syndrome, or Addison’s disease. In animal models, GR deficiency often causes perinatal lethality, highlighting its essential developmental role.