Mineralocorticoid receptor binding, structure and function

The isolation of aldosterone 50 years ago was a critical first step in elucidating the mechanism by which corticosteroids regulate electrolyte homeostasis. The broad principles of this mechanism involving an intracellular receptor acting on specific genes to induce the expression/repression of aldosterone-induced proteins (AIP) were established 30 years ago. The cloning of the mineralocorticoid receptor (MR) has enabled studies of the subcellular mechanisms of aldosterone action, including the molecular dissection of structure-function relationships in the receptor. We have exploited the close structural and functional similarity of the MR with the glucocorticoid receptor to identify the regions in the MR that confer ligand-binding specificity. The critical region is located, not as might be expected in the ligand-binding pocket but rather on the surface of the molecule. These studies have been extended to an analysis of the interactions between the N-terminal and ligand-binding domains of the MR. In the last decade, AIP have been identified; the regulation of the genes encoding these AIP are discussed.