The effects of non-genomic glucocorticoid mechanisms on bodily functions and the central neural system. A critical evaluation of findings

Mounting evidence suggests that—beyond the well-known genomic effects—glucocorticoids affect cell function via non-genomic mechanisms. Such mechanisms operate in many major systems and organs including the cardiovascular, immune, endocrine and nervous systems, smooth and skeletal muscles, liver, and fat cells. Non-genomic effects are exerted by direct actions on membrane lipids (affecting membrane fluidity), membrane proteins (e.g. ion channels and neurotransmitter receptors), and cytoplasmic proteins (e.g. MAPKs, phospholipases, protein kinases, etc.). These actions are mediated by the glucocorticoids per se or by the proteins dissociated from the liganded glucocorticoid receptor complex. The MR and GR also activate non-genomic mechanisms in certain cases. Some effects of glucocorticoids are shared by a variety of steroids, whereas others are more selective. Moreover, “ultra-selective” effects—mediated by certain glucocorticoids only—were also shown. Disparate findings suggest that non-genomic mechanisms also show “demand-specificity”, i.e. require the coincidence of two or more processes. Some of the non-genomic mechanisms activated by glucocorticoids are therapeutically relevant; moreover, the “non-genomic specificity” of certain glucocorticoids raises the possibility of therapeutic applications. Despite the large body of evidence, however, the non-genomic mechanisms of glucocorticoids are still poorly understood. Criteria for differentiating genomic and non-genomic mechanisms are often loosely applied; interactions between various mechanisms are unknown, and non-genomic mechanism-specific pharmacological (potentially therapeutic) agents are lacking. Nevertheless, the discovery of non-genomic mechanisms is a major breakthrough in stress research, and further insights into these mechanisms may open novel approaches for the therapy of various diseases.