Mineralocorticoid receptors in the central nervous system

"Mineralocorticoid receptors (MR) in the central nervous system" is something of a misnomer, in that the sites so designated almost certainly act predominantly as high affinity receptors for glucocorticoid hormones in most areas of the brain, reflecting the equivalent affinity of MR for aldosterone, corticosterone and cortisol. In epithelial tissues, the enzyme 11 beta hydroxysteroid dehydrogenase-2 confers aldosterone-specificity on the otherwise non-selective MR, by converting physiologic glucocorticoids (but not aldosterone) to receptor-inactive 11-keto metabolites. Coding differences in guinea-pig ACTH and glucocorticoid receptors produce very high circulating free cortisol levels; guinea-pig MR have nonetheless similar high affinity for aldosterone and glucocorticoids as those in the rat, evidence for the lack of evolutionary drive towards lower affinity MR, and for an "always occupied" mode of action of CNS MR. Whether these "always occupied" MR act at composite response elements, by the formation of heterodimers with GR or other transcription factors, or by binding progesterone in the luteal phase, in pregnancy and in utero, remains to be established.