30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Mineralocorticoid receptor activation and specificity-conferring mechanisms: a brief history.

The mineralocorticoid receptor (MR) was first characterized 45 years ago (Funder 1972, Rousseau 1972), a decade and a half before its successful cloning (Arriza 1987) to which this issue of the Journal is dedicated. Aldosterone had been isolated and characterized 20 years before the MR: its initial name was electrocortin, reflecting its ability to promote electrolyte transport across epithelial membranes, rapidly changed to its familiar, current name aldosterone. What prompted the change was the finding of a unique aldehyde group at carbon18 of the steroid molecule, the physiological significance of which only became clear many years later (Edwards 1988, Funder 1988). Not surprisingly, given the rapidly established role of aldosterone in the transepithelial transport of sodium, potassium and water, was that the early running was made by nephrologists and renal physiologists. Although rapid effects of aldosterone on renal sodium transport were reported in early studies (Ganong 1958), later attention focused on the demonstration that aldosterone action could be blocked at the level of DNA transcription (by actinomycin D) or mRNA translation (by puromycin), evidence that aldosterone acted principally at the intracellular level by DNA-directed, RNA-mediated protein synthesis. This expanded the field of interest beyond the nephrologists to include cell biologists, endocrinologists and clinicians – evidence for the latter are the initial reports of dexamethasone suppressible hyperaldosteronism (Sutherland 1966, New 1967). These were published years before the receptor was characterized by high affinity, displaceable (sometimes bravely termed specific) binding of tritiated aldosterone in kidney slices from adrenalectomized rats; less convincing, in retrospect, was a similar report in rat kidney cytosol (Rousseau 1972), given the subsequent demonstration that molybdate is needed for cytosolic MR to survive in vitro (Emadian 1988). The interest of endocrinologists was kindled by the recognition that the MR was one of a family of nuclear transactiving factors, which includes glucocorticoid receptors (GR), progesterone receptors (PR), androgen receptors, and more distantly estrogen receptors and those for 1,25 dihydroxycholecalciferol. Interest was further kindled in the case of the MR by the demonstration of its presence in tissues not primarily involved in transepithelial transport – e.g., brain, heart and blood vessels (Krozowski 1981, Pearce 1987, Funder 1989). At the same time a series of studies showed that MR had not only (high picomolar) affinity for aldosterone, but also puzzlingly equally high affinity for cortisol, corticosterone, deoxycorticosterone and progesterone. Such studies needed to be carefully designed: transcortin in fetal calf serum lowers values for cortisol and corticosterone, and studies on progesterone binding require siliconized syringes and glassware. Neither of these latter are available in vivo, but the potent MR antagonist effect of elevated progesterone in pregnancy, to raise countervailing aldosterone levels 3–10 fold, had been noted very early and provided the point of departure for the synthesis of spironolactone (Kagawa 1957). Similarly, deoxycorticosterone had been recognized as the ‘standard’ mineralocorticoid hormone more than a decade before it was supplanted by the physiologic mineralocorticoid aldosterone. The implications of this MR promiscuity were immediately clear. In high blood flow organs, such as 234 1