Action of glucocorticoids Video

Glucocorticoids (GC) are a class of steroid hormones that bind to the glucocorticoid receptor (GR), which is present in almost every vertebrate animal cell. The name glucocorticoid (glucose + cortex + steroid) derives from their role in the regulation of the metabolism of glucose, their synthesis in the adrenal cortex, and their steroidal structure.



Mechanism of action
Transactivation

Glucocorticoids bind to the cytosolic glucocorticoid receptor (GR). This type of receptor is activated by ligand binding. After a hormone binds to the corresponding receptor, the newly-formed receptor-ligand complex translocates itself into the cell nucleus, where it binds to glucocorticoid response elements (GRE) in the promoter region of the target genes resulting in the regulation of gene expression. This process is commonly referred to as transactivation.

The proteins encoded by these upregulated genes have a wide range of effects including for example:[5]

* anti-inflammatory – lipocortin I and p11/calpactin binding protein
* increased gluconeogenesis – glucose-6-phosphatase and tyrosine aminotransferase

Transrepression

The opposite mechanism is called transrepression. The activated hormone receptor interacts with specific transcription factors (such as AP-1 and NF-κB) and prevents the transcription of targeted genes. Glucocorticoids are able to prevent the transcription of pro-inflammatory  genes, including interleukins IL-1B, IL-4, IL-5, and IL-8, chemokines, cytokines, GM-CSF, and TNFA genes.

Dissociation

The ordinary glucocorticoids do not distinguish among transactivation and transrepression and influence both the "wanted" immune and "unwanted" genes regulating the metabolic and cardiovascular functions. Intensive research is aimed at discovering selectively acting glucocorticoids that will be able to repress only the immune system.

Genetically modified mice which express a modified GR which is incapable of DNA binding are still responsive to the antiinflammatory effects of glucocorticoids while the stimulation of gluconeogenesis by glucocorticoids is blocked. This result strongly suggests that most of the desirable antiinflammatory effects are due to transrepression while the undesirable metabolic effects arise from transactivation, a hypothesis also underlying the development of selective glucocorticoid receptor agonists.

Non-genomic

Glucocorticoids have been shown to exert a number of rapid actions that are independent of the regulations of gene transcription.

Binding of corticosteroids to the glucocorticoid receptor (GR) stimulates phosphatidylinositol 3-kinase and protein kinase AKT, leading to endothelial nitric oxide synthase (eNOS) activation and nitric oxide dependent vasorelaxation.Membrane associated GR has been shown to mediate lymphocytolysis.Finally some glucocorticoids have been shown to rapidly inhibit the release of the inflammatory prostaglandin PGE2 and this effect is blocked by the glucocorticoid receptor antagonist RU-486 and this effect is not affected by protein synthesis inhibitors. This data together suggests a non-genomic mechanism of action.

Glucocorticoid. (2010, February 11). In Wikipedia, The Free Encyclopedia. Retrieved 17:23, February 27, 2010, from http://en.wikipedia.org/w/index.php?title=Glucocorticoid&oldid=343258134

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