Steroid hormones are indispensable in physical development, control of vital processes, reproduction and modulation of behavior. Lack or complete dysfunction of glucocorticoids (GC), in particular, have lethal consequences. Even a minor change in the level of circulating cortisol may have physiological and clinical significance in GChomeostasis and GC-related disorders. Knowledge of the action mechanisms of GC and analysis of their effects is therefore of essential importance, especially since natural and synthetic GC are widely used in the therapy of GC-responsive diseases. Most GC effects are assigned to the nuclear GC receptors (GR) and their co-modulators by activating or repressing gene expression. Whereas activation mainly requires DNA binding of the GR-ligand complex, repression is usually mediated by protein-protein interaction with other transcription factors, termed transcriptional cross-talk. In addition to the classical and the cross-talk mode of GR actions, GC also functionally interact with plasma membrane (PM) binding sites at the surface of target cells and initiate a number of so called rapid non-genomic effects similar to signaling by peptide hormones. It is generally believed that no functional link exists between the PM-related non-genomic steroid responses and the nuclear receptor-related genomic effects. However, some reports indicate that rapid responses can modulate the genomic pathway of steroids or enhance/impair gene activation. The corresponding PM-receptors may be (splice) variants of the GR or GR-unrelated proteins that cooperate with the GR or not. A PM-located protein in rat and human liver cells, SHREC (Steroid Hormone Recognition and Effector Complex), represents a pivotal link in nongenomic and genomic modes of GC-signal propagation. The different modes of action of GC and the various PMreceptors are reviewed with emphasis on the basic biological functions as well as the physiological and clinical significance of these "extranuclear" proteins. In addition, a three-dimensional computational model of SHREC is presented, which may provide the possibility for rational design of tailor made GC to improve therapy of GC related diseases.
Keywords: Glucocorticoids, genomic and rapid non-genomic effects, membrane initiated steroid signaling, receptor, mGR, steroid hormone recognition and effector complex, signal pathways cross-talk, plasma membrane, automated receptor modeling approach, GC-dependent diseases (autoimmune diseases, SLE, asthma)
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