Activation of the ligand-mineralocorticoid receptor functional unit by ancient, classical, and novel ligands. Structure-activity-relationship

MARIO D. GALIGNIANA; GRACIELA PIWIEN PILIPUK

Vitamins and Hormones

Elsevier Science

Lugar: New York; Año: 2004; p. 31 - 68

The mineralocorticoid effect on epithelial cells is the resultant of an intricate net of biochemical regulations that ultimately leads to the maintenance of electrolyte homeostasis. Two key protagonists in this plot are the ligand -that broadcasts the information- and the receptor -that functions as a receiver and transducer-. Therefore, the responsibility for the final biological effect is not limited to each individual component but both of them, so they constitute a functional unit. In addition, several pre-receptor regulatory mechanisms are also determinant factors for the final biological response. Because steroids are present in both animals and plants and are derived from common precursors, it is intriguing how these simple molecules have acquired specialization to shape biological development and differentiation. This is particularly true for the function of aldosterone in mammals, which is mimicked by glucocorticoids or progesterone in some particular cases. Inasmuch as the most potent mineralocorticoid in nature, aldosterone, shows a poorly angled steroid nucleus at the A/B-ring junction, and because steroids that possess identical functional groups and different steroidal frame elicit different mineralocorticoid effect, we postulate that a planar conformation of the ligand is a key requirement to acquire potent sodium retention properties. The model takes into consideration all the mechanisms involved in the regulation of the final biological effect, although it does not provide a definitive answer to the original question. It is also discussed how the use of novel mineralocorticoid ligands may shed light on the still obscure mechanism of action of the mineralocorticoid receptor.