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Endocrinology Jan 2005
Review
Topics: Animals; Fishes; Mineralocorticoids; Oncorhynchus mykiss; Protein Isoforms; Receptors, Mineralocorticoid
PubMed: 15601905
DOI: 10.1210/en.2004-1390 -
Steroids Apr 1996The syndrome of apparent mineralocorticoid excess (AME) is a heritable form of hypertension due to an inborn error of cortisol metabolism and is characterized by... (Review)
Review
The syndrome of apparent mineralocorticoid excess (AME) is a heritable form of hypertension due to an inborn error of cortisol metabolism and is characterized by hypokalemia and low renin levels despite subnormal or normal levels of aldosterone and other known mineralocorticoids. The syndrome is attributable to congenital deficiency of the enzyme 11 beta-hydroxydehydrogenase (11 beta-HSD), which converts cortisol (F) to biologically inactive cortisone. This results in a prolonged half-life of F, which acts at the kidney level as a potent mineralocorticoid (MC). In fact, both F and aldosterone have similar affinities in vitro for type I MC receptor (MR), and 11 beta-HSD activity protects the MR in vivo from the higher circulating levels of F. The biochemical marker of this disorder is an increased ratio of tetrahydrocortisol (THF) + allo-THF/tetrahydrocortisone (THE) in the urine, which has been found in more than 20 patients described to date, together with evidence of a more general defect in steroid ring A reduction. Only a few cases (the so-called type II form) described in Italy differ from the classic form having a normal THF/THE ratio, but in both forms the ratio of free urinary F/E has recently been found to be similarly high. Dexamethasone is the treatment of choice but is often inadequate in long term control of high blood pressure. Acquired forms of AME are those consequent on abuse of licorice or carbenoxolone, which both inhibit 11 beta-HSD; the latter also inhibits the reverse 11-oxoreductase reaction leading to somewhat different abnormalities of urinary cortisol/cortisone. So far, two isoenzymes of 11 beta-HSD have been purified and cloned; 11 beta-HSD type 1 is NADP-dependent, abundant in liver, lung, and testis, and catalyzes both 11 beta-dehydrogenation and 11 beta-oxoreduction; no mutation in its gene was detected in patients with AME. A second NAD-dependent isoenzyme is present in kidney and placenta and catalyzes dehydrogenation only. Very recently (1995) two groups have independently demonstrated the presence of mutations in its gene, located in chromosome 16q22. New and co-workers found a point mutation in exon 6 of two affected siblings of an Iranian family, while White and co-workers in parallel studies showed point mutations or small deletions in both alleles in nine unrelated patients; importantly, expression studies showed minimal or absent activity for almost all the mutant sequences. No definite mutations have been so far identified in patients with AME type II. AME is thus the third single gene cause of human hypertension to be described, after glucocorticoid remediable aldosteronism in 1992 and Liddle's syndrome in 1994.
Topics: Child, Preschool; Dexamethasone; Humans; Hydrocortisone; Hypertension; Hypokalemia; Infant; Mineralocorticoids
PubMed: 8732999
DOI: 10.1016/0039-128x(96)00012-8 -
American Journal of Physiology. Renal... Feb 2001Aldosterone regulates renal sodium reabsorption through binding to the mineralocorticoid receptor (MR). Because the glucocorticoid receptor (GR) is expressed together... (Review)
Review
Aldosterone regulates renal sodium reabsorption through binding to the mineralocorticoid receptor (MR). Because the glucocorticoid receptor (GR) is expressed together with the MR in aldosterone target cells, glucocorticoid hormones bound to GR may also intervene to modulate physiological functions in these cells. In addition, each steroid can bind both receptors, and the MR has equal affinity for aldosterone and glucocorticoid hormones. Several cellular and molecular mechanisms intervene to allow specific aldosterone regulatory effects, despite the large prevalence of glucocorticoid hormones in the plasma. They include the local metabolism of the glucocorticoid hormones into inactive derivatives by the enzyme 11beta-hydroxysteroid dehydrogenase; the intrinsic properties of the MR that discriminate between ligands through differential contacts; the possibility of forming homo- or heterodimers between MR and GR, leading to differential transactivation properties; and the interactions of MR and GR with other regulatory transcription factors. The relative contribution of each of these successive mechanisms may vary among aldosterone target cells (epithelial vs. nonepithelial) and according to the hormonal context. All these phenomena allow fine tuning of cellular functions depending on the degree of cooperation between corticosteroid hormones and other factors (hormonal or tissue specific). Such interactions may be altered in pathophysiological situations.
Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 2; 11-beta-Hydroxysteroid Dehydrogenases; Aldosterone; Animals; Glucocorticoids; Humans; Hydroxysteroid Dehydrogenases; Kidney; Mineralocorticoids; Receptors, Glucocorticoid; Receptors, Mineralocorticoid; Receptors, Steroid
PubMed: 11208593
DOI: 10.1152/ajprenal.2001.280.2.F181 -
Hormone Research 2003
Topics: Humans; Hypertension; Mineralocorticoids; Receptors, Mineralocorticoid
PubMed: 12566721
DOI: 10.1159/000067845 -
Pharmacological Reviews Mar 1994
Review
Topics: Animals; Base Sequence; Humans; Mineralocorticoids; Molecular Sequence Data; Receptors, Mineralocorticoid
PubMed: 8190750
DOI: No ID Found -
The Journal of Endocrinology Jul 2017The mineralocorticoid receptor (MR) is descended from a corticoid receptor (CR), which has descendants in lamprey and hagfish, cyclostomes (jawless fish), a taxon that... (Review)
Review
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 chimeras. 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. Further divergence of the MR and GR in terrestrial vertebrates, which synthesize aldosterone, led to emergence of aldosterone as a selective ligand for the MR. 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 3-ketosteroids by the MR in terrestrial vertebrates and ray-finned fish, as well as the basis for binding of some glucocorticoids by human MR and other vertebrate MRs.
Topics: Amino Acid Sequence; Animals; Evolution, Molecular; Gene Expression Regulation; Humans; Mineralocorticoids; Receptors, Mineralocorticoid
PubMed: 28468932
DOI: 10.1530/JOE-16-0661 -
The Journal of Endocrinology Jul 2017The cloning of the mineralocorticoid receptor (MR) 30 years ago was the start of a new era of research into the regulatory processes of MR signalling at target genes in... (Review)
Review
The cloning of the mineralocorticoid receptor (MR) 30 years ago was the start of a new era of research into the regulatory processes of MR signalling at target genes in the distal nephron, and subsequently in many other tissues. Nuclear receptor (NR) signalling is modified by interactions with coregulatory proteins that serve to enhance or inhibit the gene transcriptional responses. Over 400 coregulatory proteins have been described for the NR super family, many with functional roles in signalling, cellular function, physiology and pathophysiology. Relatively few coregulators have however been described for the MR although recent studies have demonstrated both ligand and/or tissue selectivity for MR-coregulator interactions. A full understanding of the cell, ligand and promoter-specific requirements for MR-coregulator signalling is an essential first step towards the design of small molecular inhibitors of these protein-protein interactions. Tissue-selective steroidal or non-steroidal modulators of the MR are also a desired therapeutic goal. Selectivity, as for other steroid hormone receptors, will probably depend on differential expression and recruitment of coregulatory proteins.
Topics: Animals; Gene Expression Regulation; Mineralocorticoids; Receptors, Mineralocorticoid; Signal Transduction
PubMed: 28634265
DOI: 10.1530/JOE-17-0060 -
Biochemical Pharmacology Nov 2008Treatment of so-called civilization diseases, including some forms of cancer, immune-related diseases and metabolic disorders, represent a major challenge in the... (Review)
Review
Treatment of so-called civilization diseases, including some forms of cancer, immune-related diseases and metabolic disorders, represent a major challenge in the industrialized world. In addition to genetic predisposition, behavior and exposure to xenobiotics contribute to these diseases. Here, we review existing evidence for an association of environmental chemicals with disturbed glucocorticoid- and mineralocorticoid-regulated physiological processes. Impaired activity of glucocorticoids and mineralocorticoids can contribute to several diseases, including neurological diseases, immune disorders and metabolic syndrome. Recent studies provide evidence for the existence of environmental chemicals that are able to disrupt the function of these hormones at different levels of their action. Therefore, potential interferences with these hormones should be considered for safety assessment of chemicals. Compared with the extensive knowledge on chemicals interfering with estrogen or androgen responses, the study of glucocorticoid and mineralocorticoid disruptors is an emerging field of research, and the identification of relevant xenobiotics and their underlying mechanisms of toxicity remains a major challenge.
Topics: Animals; Environmental Pollutants; Glucocorticoids; Humans; Immune System Diseases; Metabolic Syndrome; Mineralocorticoids; Nervous System Diseases
PubMed: 18765234
DOI: 10.1016/j.bcp.2008.07.019 -
Kidney International Apr 2000Aldosterone exerts its biological effects through binding to mineralocorticoid receptor (MR). Ligand binding induces a receptor transconformation within the... (Review)
Review
Aldosterone exerts its biological effects through binding to mineralocorticoid receptor (MR). Ligand binding induces a receptor transconformation within the ligand-binding domain and dissociation of associated proteins from the receptor. The ligand-activated receptor binds as a dimer to the response elements present in the promoter region of target genes and initiates the transcription through specific interactions with the transcription machinery. The glucocorticoid hormone cortisol binds to the human MR (hMR) with the same affinity as aldosterone, but is less efficient than aldosterone in stimulating the hMR transactivation. The antimineralocorticoid spirolactones also bind to the hMR but induce a receptor conformation that is transcriptionally silent. In this report, we describe the key residues involved in the recognition of agonist and antagonist ligands and propose a two-step model with a dynamic dimension for the MR activation. In its unliganded state, MR is in an opened conformation in which folding into the ligand-binding competent state requires both the heat shock protein 90 and the C-terminal part of the receptor. An intermediate complex is generated by ligand binding, leading to a more compact receptor conformation. This transient complex is then converted to a transcriptionally active conformation in which stability depends on the steroid-receptor contacts.
Topics: Amino Acids; Humans; Ligands; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Protein Folding; Receptors, Mineralocorticoid
PubMed: 10760050
DOI: 10.1046/j.1523-1755.2000.00958.x -
Pharmacology & Therapeutics Dec 1999The adrenal cortex elaborates two major groups of steroids that have been arbitrarily classified as glucocorticoids and mineralocorticoids, despite the fact that... (Review)
Review
The adrenal cortex elaborates two major groups of steroids that have been arbitrarily classified as glucocorticoids and mineralocorticoids, despite the fact that carbohydrate metabolism is intimately linked to mineral balance in mammals. In fact, glucocorticoids assured both of these functions in all living cells, animal and photosynthetic, prior to the appearance of aldosterone in teleosts at the dawn of terrestrial colonization. The evolutionary drive for a hormone specifically designed for hydromineral regulation led to zonation for the conversion of 18-hydroxycorticosterone into aldosterone through the catalytic action of a synthase in the secluded compartment of the adrenal zona glomerulosa. Corticoid hormones exert their physiological action by binding to receptors that belong to a transcription factor superfamily, which also includes some of the proteins regulating steroid synthesis. Steroids stimulate sodium absorption by the activation and/or de novo synthesis of the ion-gated, amiloride-sensitive sodium channel in the apical membrane and that of the Na+/K+-ATPase in the basolateral membrane. Receptors, channels, and pumps apparently are linked to the cytoskeleton and are further regulated variously by methylation, phosphorylation, ubiquination, and glycosylation, suggesting a complex system of control at multiple checkpoints. Mutations in genes for many of these different proteins have been described and are known to cause clinical disease.
Topics: Amiloride; Animals; Humans; Immunohistochemistry; Mineralocorticoid Receptor Antagonists; Mineralocorticoids; Receptors, Mineralocorticoid; Sodium Channels; Sodium-Potassium-Exchanging ATPase; Structure-Activity Relationship
PubMed: 10665831
DOI: 10.1016/s0163-7258(99)00038-8