Glucocorticoid Receptor in Health and Disease

Abstract

Glucocorticoid Receptor in Health and DiseaseGlucocorticoid hormones are essential for life, have a vital place in the treatment of inflammatory and autoimmune diseases and are increasingly implicated in the pathogenesis of a number of common disorders. Their action is mediated by an intracellular receptor protein, the glucocorticoid receptor (GR), functioning as a ligand-inducible transcription factor. Multiple synthetic glucocorticoids are used as potent antiinflammatory and immunosuppressive agents, but their therapeutic usefulness is limited by a wide range and severity of side-effects. One of the most important pharmaceutical goals has been to design steroidal and non-steroidal GR ligands with profound therapeutic efficacy and reduced unwanted effects. The therapeutic benefit of glucocorticoid agonists is frequently compromised by resistance to glucocorticoids, which may depend on: access of the hormones to target cells, steroid metabolism, expression level and isoform composition of the GR protein, mutations and polymorphisms in the GR gene and association of the receptor with chaperone proteins. The major breakthrough into the critical role of glucocorticoid signaling in the maintenance of homeostasis and pathogenesis of diseases, as well as into the molecular mechanisms underlying the therapeutic usefulness of antiinflammatory drugs acting through the GR is expected to result from the current progress in large-scale gene expression profiling technologies and computational biology.

Morphofunctional Characteristics of Pituitary Adrenocorticotropes in An Animal Model of Heat Stress

“…stress-sensitive paraventriculo-infundibular corticotrophin-releasing hormone (CRH) and arginine-vasopressin (AVP) producing neurons (3,4). ACTH, released into the peripheral circulation in response to stress, stimulates the synthesis and secretion of adrenal glucocorticoids (3,5,6). Studies carried out with rats demonstrate that the feedback effects between some hypothalamic peptides (CRH, AVP) and adrenocor tical steroids influence the morphology, size, and number of pituitary ACTH cells (7,8).…”

Sweet-P inhibition of glucocorticoid receptor β as a potential cancer therapy

“…The gene that codes for GR in humans is found on the q arm of chromosome 5 [5,6] , and is a single GR gene that is alternative spliced to give rise to at least five isoforms α, β, γ, A, and P [5,[7][8][9] . GRα and GRβ have been the most investigated isoforms.…”

“…GRα contains an additional fifty amino acids derived from the proximal portion of exon 9 that constructs helix 12 for ligand binding. GRβ does not have the capacity to bind glucocorticoids because of an additional fifteen amino acids derived from the distal portion of exon 9 that causes a degenerate helix 12 [5,9,11,12] . The alternative splicing mechanism in humans is different than in mouse [11] , rat [13] , and zebrafish [14] , but in these species that GRβ has been identified, GRα and GRβ are identical through exon 8 with an addition of an alternatively spliced intron 8.…”

Correlation Between Cytokine Levels in Nasal Fluid and Scored Clinical Parameters in Patients with Nasal Polyposis

“…It is characterized by intermittent obstruction and inflammatory changes of airways and bronchial hyperresponsiveness [6]. It is known that the pathogenesis as well as pathophysiology of this disease are associated with alterations of glucocorticoid receptor function and also with persistent pulmonary inflammation, the important mediators of which are reactive oxygen and nitrogen [7].…”