Why are mineralocorticoid receptors so nonselective?

Mineralocorticoid receptors (MR) bind aldosterone, cortisol, and progesterone with equal high affinity. Attention has focused on the role of MR in epithelial fluid and electrolyte homeostasis; from a variety of studies, however, MR are largely constitutively occupied by cortisol, with aldosterone an evolutionary latecomer, and MR pressed into service in epithelia to respond selectively to aldosterone through the co-expression of 11beta hydroxysteroid dehydrogenase type 2. The pathophysiologic--and to a lesser extent the physiologic--roles of constitutively cortisol-occupied MR in nonepithelial tissues (eg, cardiomyocytes, neurons) are beginning to be delineated; the implications of the maintained high affinity of MR for progesterone, and their possible role as primarily progesterone sensors in reproductive (and other) tissues, await exploration.