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The Roles of Plasma Binding and Receptor Specificity in the Mineralocorticoid Action of Aldosterone¹

Cardiovascular Research Institute and the Departments of Medicine, and of Biochemistry and Biophysics, University of California School of Medicine San Francisco

Abstract

The current hypothesis of the mechanism of action of aldosterone includes an initiating step of binding of the steroid to stereospecific receptor proteins in target tissues. In view of the very low circulating levels of aldosterone relative to other adrenal steroids, there must exist potent specificity—conferring mechanisms to insure appropriate aldosterone occupancy of mineralocorticoid receptors. Two specificity—conferring mechanisms are described which are posited to allow aldosterone occupancy of its appropriate receptor.In vitro, renal aldosterone binding sites are shown to fall into two classes. Those with a higher affinity for aldosterone—K_dlss (37 C) 5X10^-10—are termed Type I; those with a lower affinity—K_diss (37 C) 2.5 X lO^-8— Type II. Desoxycorticosterone (DOC) has 80% the affinity of aldosterone for both sites. Corticosterone (B) has a high affinity for Type II sites, but less than 2% of the affinity of aldosterone for Type I. From the relative affinities of the three steroids for Type I, these sites are postulated to be mineralocorticoid receptors. However, even taking these relative affinities into account, the differences in plasma levels of aldosterone, B, and DOC are such that the mineralocorticoid receptors would be largely, and presumably inappropriately, occupied in vivo by B and DOC. On the basis of a series of in vivo infusion experiments, the second specificity—conferring mechanism, necessary to allow aldosterone occupancy of renal mineralocorticoid receptors, is demonstrated to be the preferential (B > DOC > > aldosterone) plasma binding of the potential competing steroids. The ability of aldosterone to occupy the mineralocorticoid receptors under physiological conditions is therefore a function both of the very low affinity of the Type I receptors for corticosterone, and the extensive, preferential plasma binding of DOC and corticosterone. (Endocrinology 92: 994, 1973)

Footnotes

¹ With the financial support of USPHS, National Heart and Lung Institute, Grant No. HL–06285.

² During the tenure of a National Heart Foundation of Australia Overseas Research Fellowship.

³ During the tenure of a post-doctoral traineeship provided by USPHS National Heart and Lung Institute, Grant No. HL–05725.

Received July 3, 1972.

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