Intracellular Glucocorticoid Signaling: A Formerly Simple System Turns Stochastic

Glucocorticoids contribute fundamentally to the maintenance of basal and stress-related homeostasis in all higher organisms. The major roles of these steroids in physiology are amply matched by their remarkable contributions to pathology. Glucocorticoids influence about 20% of the expressed human genome, and their effects spare almost no organs or tissues. For many years we thought that the numerous actions of glucocorticoids were mediated by a single receptor molecule: the classic glucocorticoid receptor (GR) isoform alpha, a complex, multifunctional domain protein, operating as a ligand-dependent transcription factor. The GR gene, however, encodes two 3' splicing variants, GRalpha and GRbeta, from alternative use of two distinct terminal exons (9alpha and 9beta), and each variant mRNA is translated from at least eight initiation sites into multiple GRalpha and possibly GRbeta isoforms, amounting to a minimum of 16 GR monomers and 256 different homo- or heterodimers. The translational GRalpha isoforms may be produced variably in target tissues, have varying intrinsic transcriptional activities, and influence different complements of glucocorticoid-responsive genes. It is likely that expression and functional differences might also be present between the putative GRbeta translational isoforms. The presence of multiple GR monomers and dimers in different quantities with quantitatively and qualitatively different transcriptional activities suggests that the glucocorticoid signaling system is highly stochastic.