The mineralocorticoid receptor (MR) mediates the sodium-retaining effects of aldosterone in the kidney, salivary glands, sweat glands, and colon. The human MR gene was cloned in 1987 and bears structural and functional kinships to the glucocorticoid receptor.12 The gene encoding the receptor spans 60-90 kb on chromosome 4q31.2,13,14 and contains 10 exons including two exons (1a and 1p) that encode different 5' untranslated sequences whose expression is controlled by two different promoters.15 A missense mutation (MRS810L) in the ligand-binding domain of the mineralocorticoid receptor causes an autosomal dominant form of early onset hypertension.16,17 This mutation was discovered in a 15-year-old boy with severe hypertension and tests of his family revealed 11 of 23 relatives had the mutation, all of whom had been diagnosed with severe hypertension before they were 20 years old. The mutation results in constitutive MR receptor activity in the absence of added steroid, but normal activation by al-dosterone, while progesterone and other clinically used corticocoid antagonists, such as spironolactone lacking 21-hydroxyl groups, become agonists. Since progesterone levels are usually elevated by as much as 100-fold during pregnancy, reaching concentrations of 500 nM, the investigators thought that pregnant females with the S810L variant isoform of the MR receptor might develop severe hypertension. Two MR carriers of the family mentioned above had undergone five pregnancies, all of which were complicated by exacerbation of hypertension. The absence of proteinuria, edema, or neurological changes excluded preeclampsia.
Molecular modeling and site-directed mutagenesis demonstrated that the leu-cine (L810) residue in the 5 helix of the ligand-binding MR domain makes a new van der Waals interaction with asparagine (A773) in helix 3. This interaction eliminates the requirement for the 21-hydroxy group of aldosterone to interact with N770 in helix 3. An effective therapy to correct this disorder has not been developed, but since every other steroid hormone receptor as well as several other nuclear hormone receptors has leucine-alanine or methionine-glycine pairs at homologous positions in helix 5 and helix 3, molecular modeling suggests a general approach to the creation of a steroid receptor antagonist.18
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Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...