The role of 11β-hydroxysteroid dehydrogenases in the regulation of corticosteroid activity in the brain

Abstract: Glucocorticoids influence a broad range of central nervous system (CNS) processes, altering neurotransmission, electrophysiological activity, metabolism, cell division and survival. These actions are mediated by nuclear glucocorticoid and mineralocorticoid receptors, which regulate transcription of target genes. The amount of steroid available to activate these receptors is not only dependent on circulating hormone levels but also, crucially, on intracellular, pre-receptor metabolism of glucocorticoids by 11β-hydroxysteroid dehydrogenases (11β-HSDs). There are two distinct 11β-HSD isozymes, the products of distantly related genes, 11β-HSD type 2 is a high-affinity dehydrogenase that rapidly inactivates glucocorticoids to inert 11-keto-derivatives, thus ‘protecting’ co-localised receptors from the ligand. In contrast, in many intact cells and whole tissues, 11β-HSD type 1 catalyses the reverse reaction, regenerating active glucocorticoids from circulating inert forms, locally amplifying glucocorticoid actions. This review highlights recent results that have illuminated the important and very different roles that the two isozymes play in the brain.