Autoregulation of corticosteroid receptors. How, when, where, and why?

The corticosteroid receptors, including the glucocorticoid and mineralocorticoid receptors (GR and MR, respectively), are subject to ligand-mediated autoregulation like other members of the steroid receptor gene superfamily. Since it is the level of expression of these closely related intracellular receptors that determines cellular sensitivity to adrenal glucocorticoid and mineralocorticoid hormones, homologous as well as potential heterologous regulation of GR and MR levels constitute physiologically important homeostatic events. Although these autoregulatory responses are often exhibited in the form of receptor down-regulation (negative autoregulation), hormone-mediated up-regulation (positive autoregulation) has also been documented. Clearly, the extent as well as direction of hormone-mediated autoregulation of corticosteroid receptors vary considerably between different target tissues and cell types and may be altered during development or as a consequence of aging or disease state. Although historically the homologous as well as heterologous regulation of GR and MR were evaluated exclusively at the ligand binding levels, the cloning of the genes for these corticosteroid receptors has facilitated detailed analysis of hormonal regulation at the message and protein levels. Data generated in numerous laboratories have demonstrated that this regulation may be mediated at one or more molecular levels, including: the transcriptional level, as evidenced by the ability of ligand-receptor complexes to decrease the rate of receptor gene transcription; the posttranscriptional level, as evidenced by the ability of some ligands to alter the stability of their own receptor message; and at the posttranslational level, as evidenced by the ability of agonists to shorten the half-life of their own receptor protein. In this review we have focused on several basic questions (how, when, where, and why?) concerning this hormonal regulation of corticosteroid receptors. Clearly, many of these key questions concerning autoregulation of GR and MR levels remain unanswered and further studies in this area will enhance our understanding of the mechanisms involved in these cellular events.