Mechanism of Action of Corticosteroids

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Chapter: Essential pharmacology : Corticosteroids

Corticosteroids penetrate cells and bind to a high affinity cytoplasmic receptor protein → a structural change occurs in the steroid receptor complex that allows its migration into the nucleus and binding to glucocorticoid response elements (GRE) on the chromatin → transcription of specific mRNA → regulation of protein synthesis


MECHANISM OF ACTION AT CELLULAR LEVEL

 

Corticosteroids penetrate cells and bind to a high affinity cytoplasmic receptor protein a structural change occurs in the steroid receptor complex that allows its migration into the nucleus and binding to glucocorticoid response elements (GRE) on the chromatin transcription of specific mRNA regulation of protein synthesis. This process takes at least 30–60 min : effects of corticosteroid are not immediate, and once the appropriate proteins are synthesized—effects persist much longer than the steroid itself. In many tissues, the overall effect is catabolic, i.e. inhibition of protein synthesis. This may be a consequence of steroid directed synthesis of an inhibitory protein.

 

The glucocorticoid receptor (GR) is very widely distributed (in practically all cells). It has been cloned and its structure determined; made up of ~ 800 amino acids.

 

Several coactivators and corepressors modulate the interaction of liganded GR with the GREs, altering the intensity of response.

 

Because the GR largely maintains uniformity throughout the body, tissue specificity is not exhibited by different glucocorticoids, and all members produce the same constellation of effects.

 

The functional scheme of glucocorticoid receptor is presented in Fig. 4.9. Direct evidence of gene expression mediated action has been obtained for actions listed in the box.

 

Some actions of corticoids are exerted more rapidly (like inhibition of ACTH release from pituitary). These may be mediated by a cell membrane receptor or a different mechanism not involving protein synthesis.

 

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