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The corticosteroid hormones cortisol and corticosterone are secreted by the adrenal gland in response to stress. They have profound effects on brain function, which are mediated by the related mineralocorticoid (MR) and glucocorticoid (GR) receptors. The MR and GR are ligand-activated transcription factors and exert different, sometimes opposing effects on the brain. The balance between these two receptor activities is considered essential for appropriate corticosteroid signalling and health. An exciting recent insight in steroid biology is that the nature and magnitude of steroid receptor-mediated responses depend not only on ligand and receptor availability, but also in a critical manner on the presence of downstream mediator proteins (coregulators), such as the steroid receptor coactivators and nuclear receptor corepressors. Members of the coregulator families differ in their specific interactions with steroid receptors, as well as in their distribution throughout the brain and pituitary. The activity of these proteins can be regulated both at the expression level, and by post-translational modifications. These characteristics make coregulator proteins of outstanding interest as determinants of receptor, cell and state-dependent effects of MR and GR signalling (and steroid receptor signalling in general) in the brain.