Relative contribution of molecular mechanisms to cumulative ligand-mediated downregulation of GRα.

Central to the pharmacological use of glucocorticoids (GCs) is the availability of the glucocorticoid receptor alpha (GRα). However, chronic GC therapy often results in the ligand-mediated downregulation of the GRα, and the subsequent development of an acquired GC resistance. While studies have demonstrated the dimerization-dependent downregulation of GRα, as well as the molecular mechanisms through which ligand-mediated downregulation occurs, little is known regarding the relative contribution of these molecular mechanisms to the cumulative ligand-mediated downregulation of the receptor, especially within an endogenous system. Thus, to probe this, the current study evaluates the conformational-dependent regulation of GRα protein using mouse embryonic fibroblast (MEF) cells containing either wild type GRα (MEFwt) or the dimerization deficient GRα mutant (MEFdim) and inhibitors of transcription, translation, and proteasomal degradation. Results show that the promotion of GRα dimerization increases the downregulation of the receptor via two main mechanisms, proteasomal degradation of the receptor protein, and downregulation of GRwt mRNA transcripts. In contrast, when receptor dimerization is restricted these two mechanisms play a lesser role and results suggest that stabilization of GRα protein by non-coding RNAs may potentially be the major regulatory mechanism. Together, these findings clarify the relative contribution of the molecular mechanisms involved in ligand-mediated downregulation of GRα and provides pharmacological targets for the development of GRα ligands with a more favourable therapeutic index.

Acquired Glucocorticoid Resistance Due to Homologous Glucocorticoid Receptor Downregulation: A Modern Look at an Age-Old Problem.

For over 70 years, the unique anti-inflammatory properties of glucocorticoids (GCs), which mediate their effects via the ligand-activated transcription factor, the glucocorticoid receptor alpha (GRα), have allowed for the use of these steroid hormones in the treatment of various autoimmune and inflammatory-linked diseases. However, aside from the onset of severe side-effects, chronic GC therapy often leads to the ligand-mediated downregulation of the GRα which, in turn, leads to a decrease in GC sensitivity, and effectively, the development of acquired GC resistance. Although the ligand-mediated downregulation of GRα is well documented, the precise factors which influence this process are not well understood and, thus, the development of an acquired GC resistance presents an ever-increasing challenge to the pharmaceutical industry. Recently, however, studies have correlated the dimerization status of the GRα with its ligand-mediated downregulation. Therefore, the current review will be discussing the major role-players in the homologous downregulation of the GRα pool, with a specific focus on previously reported GC-mediated reductions in GRα mRNA and protein levels, the molecular mechanisms through which the GRα functional pool is maintained and the possible impact of receptor conformation on GC-mediated GRα downregulation.