Evolution of the Mineralocorticoid Receptor: Sequence, Structure and Function

Abstract

Abstract. The mineralocorticoid receptor (MR) is descended from a corticoid receptor (CR),which has descendants in lamprey and hagfish, cyclostomes (jawless fish), a taxon that evolved at the base of the vertebrate line. A distinct MR and GR first appear in cartilaginous fishes (Chondrichthyes), such as sharks, skates, rays and chimaeras. Skate MR has a strong response to corticosteroids that are mineralocorticoids and glucocorticoids in humans. The half-maximal responses (EC50s) for skate MR for the mineralocorticoids aldosterone and 11-deoxycorticosterone are 0.07 nM and 0.03 nM, respectively. EC50s for the glucocorticoids cortisol and corticosterone are 1 nM and 0.09 nM, respectively. The physiological mineralocorticoid in ray-finned fish, which do not synthesize aldosterone, is not fully understood because several 3-ketosteroids, including cortisol, 11-deoxycortisol, corticosterone, 11-deoxycorticosterone and progesterone are transcriptional activators of fish MR. Divergence of the MR and GR in terrestrial vertebrates, which synthesize aldosterone, led to increased selectivity of the MR for aldosterone, coupled with a diminished response to cortisol and corticosterone. Here, we combine sequence analysis of the CR and vertebrate MRs and GRs, analysis of crystal structures of human MR and GR and data on transcriptional activation by 3-ketosteroids of wild-type and mutant MRs and GRs to investigate the evolution of selectivity for

NR3C2 gene polymorphism is associated with risk of gestational hypertension in Han Chinese women

“…[7] The MR is expressed in numerous epithelial tissues, such as kidneys, salivary glands, sweat glands, and intestines, and promotes epithelial sodium reabsorption and potassium excretion to regulate electrolyte balance and blood pressure. [8,9] The MR is encoded by the NR3C2 gene, which is located in the q31.1 region of human chromosome 4. The gene has a length of 400 kb and includes 9 exons.…”