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.