Mineralocorticoid selectivity: Molecular and cellular aspects

Aldosterone acts in mineralocorticoid-sensitive cells by binding to the min eralocorticoid receptor (MR). Because the MR displays similar affinity for aldosterone and glucocorticoid hormones and because these latter hormones a re 100- to 1000-fold more abundant than aldosterone in the plasma, mechanis ms are required to avoid permanent illicit occupancy of MR by glucocorticoi d hormones. The main mechanism of mineralo-corticoid selectivity is enzymat ic: the 11 beta hydroxysteroid dehydrogenase (HSD2) metabolizes glucocortic oid hormones into derivatives with a low affinity for MR. The cell biology and regulation of HSD2 are reviewed in this article. as well as its implica tions in human hypertension. Other factors play a role in mineralocorticoid selectivity: the MR itself. the possibility to form homodimers (MR-MR), or heterodimers (with the glucocorticoid receptor). All of these cellular eve nts participate to successive dynamic equilibriums, which allow fine tuning of transcriptional regulation of target genes, depending on the target tis sue and the hormonal status.