Mechanisms of ligand specificity of the mineralocorticoid receptor

Abstract

The mineralocorticoid receptor (MR) differs from the other steroid receptors in that it responds to two physiological ligands, aldosterone and cortisol. In epithelial tissues, aldosterone selectivity is determined by the activity of 11b-hydroxysteroid dehydrogenase type 2, while in other tissues, including the heart and regions of the central nervous system, cortisol is the primary ligand for the MR where it may act as an antagonist. Clinical trials have demonstrated the potential of MR antagonists in the treatment of cardiovascular disease, though their use has been limited by concurrent hyperkalaemia. In order to better target the MR, an understanding of the structural determinants of tissue-and ligand-specific MR activation is needed. Interactions of the MR have been identified, which exhibit ligand discrimination and/or specificity. These interactions include those of the ligand-binding domain with ligand, with the N-terminal domain and with putative co-regulatory molecules. Agonist and antagonist binding have been characterised using chimeras between the human MR and the glucocorticoid receptor or the zebra fish MR together with molecular modelling. The interaction between the N-terminus and the C-terminus is aldosterone dependent but is unexpectedly antagonised by cortisol and deoxycorticosterone in the human MR. Nuclear receptormediated transactivation is critically dependent on, and modulated by, co-regulatory molecules. Proteins that interact with the MR in the presence of either aldosterone or cortisol, but not both, have been identified. The successful identification of ligand-specific interactions of the MR may provide the basis for the development of novel MR ligands with tissue specificity.

30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Evolution of the mineralocorticoid receptor: sequence, structure and function

“…The A/B domain contains an activation function 1 [AF1], and the E domain contains an AF2 domain , Pascual-Le Tallec & Lombes 2005, Huyet et al 2012, Faresse 2014. Each domain in MR is important for transcriptional responses (Faresse 2014, Fuller et al 2012.…”

“…Stabilizing interactions between α-helix 3 and α-helix 5 with each other and with the A and B rings on corticosteroids are important in transcriptional activation of the MR (Geller et al 2000, Bledsoe et al 2005, Fuller et al 2012, Huyet et al 2012, Baker et al 2013, as well as other 3-ketosteroid receptors. Consistent with the common ancestry of the MR, GR, PR, AR and structural similarities of the A and B rings in their canonical ligands, some key amino acids in the MR are conserved in the GR, PR, AR and CR , Baker et al 2013, Mani et al 2016.…”

“…9). Differences in the conformation of AF2 may be important in selective binding of coactivators to MR and GR (Hultman et al 2005, Hu & Funder 2006, Baker et al 2007, Yang & Young 2009, Fuller et al 2012, Baker et al 2013). …”

Aldosterone is synthesized in and activates bulbospinal neurons through mineralocorticoid receptors and ENaCs in the RVLM

“…In addition to aldosterone, glucocorticoids are also known to bind to MRs and activate them. 32,33 Thus, to evaluate endogenously produced aldosterone, we performed an FAD286 superfusion. As a result, all five RVLM neurons became hyperpolarized (Figures 5Aa, b and B Table 1A), suggesting the existence of aldosterone in the brainstem, including the RVLM region.…”

Some Aspects of Steroid Regulation in Teleosts

“…Например, в некоторых клетках MR ко-локализованы с ферментом 11β-гидроксистер оиддегидрогеназой типа 2 (HSD112b), которая селективно инактивирует кортизол и кортикос-терон, но не альдостерон [Funder et al, 1988]. Существуют и другие механизмы инактивации кортизола [Cooke et al, 1988;Fuller et al, 2012]. Предполагается, что в тканях, в которых MR присутствуют без подобных механизмов, они действуют как высокоаффинные рецепторы кортизола Tokarz et al, 2013a].…”