MR signaling
MR signaling involves four generally defined interactions (ligand binding, direct and indirect DNA binding, inter domain interactions and coregulatory interactions) (Poulsen et al. , 2018; Rivers et al. , 2019) (Poulsen et al 2018; Rivers 2019), but our mechanistic understanding is incomplete (Fuller et al. , 2021). The MR harbors three main functional domains: a N-terminal domain (NTD) with a intrinsically disordered N terminus, a DNA-binding domain (DBD), and a C-terminal ligand-binding domain (LBD) (linked to the DBD via a ‘hinge region’ (Huang, Chandra and Rastinejad, 2010)). Unliganded MR is mostly cytosolic within a HSP90-FKBP51 containing multiprotein complex. Ligand (agonist) binding induces changes to the complex and subsequent nuclear translocation (Davies, Ning and Sanchez, 2002; Gallo et al. , 2007; Wang et al. , 2007). Now nuclear, MR dissociates from its chaperone HSP90 to form homo- (Liu et al. , 1996) or MR-GR hetero-dimers (Mifsud and Reul, 2016; Rivers et al. , 2019; van Weert et al. , 2019) that bind GREs of target genes (Koninget al. , 2019). In the brain, interactions with GREs seem to predominate over other potential types of interactions with the RNA (Le Billan et al. , 2015; van Weert et al. , 2017). MR, GR, and progesterone receptor (PR) can all bind GRE sequences, and nearby binding of other transcription factors can induce specificity as has been observed for NeuroD proteins and MR (Hudson, Youn and Ortlund, 2014; Le Billan et al. , 2015; van Weert et al. , 2017). Nevertheless, steroid receptors share GRE-driven targets genes, and MR regulation of FKBP5 abundance is in fact a mechanism by which GR sensitivity can be affected (Hartmann et al. , 2021).
At the DNA the specific ligand induced conformational changes facilitate recruitment of coregulatory proteins and interactions explicit to the cell type and regulate gene expression (Fuller, Yang and Young, 2017). Interestingly, aldosterone selectively induces an interaction between the NTD and the C-terminus (N/C) of the LBD, defining the ligand response (Pippal et al. , 2009). Lastly, MR (and GR) activity differs by varying N-terminus lengths that result from alternative mRNA translation (Faresse, 2014). Our current understanding of modulation of all mechanisms above, via post-translational modifications of MR and its interacting partners (Jiménez-Canino et al. , 2017), and of their upstream regulatory pathways is limited for the brain, despite its likely relevance.