Future perspectives
The role of MR in the initial physiological and behavioural reactions to
novel circumstances or stressors, are crucial for an adaptive stress
response (Vogel et al. , 2016; de Kloet and Joëls, 2017) and, for
dynamic and allostatic system homeostasis of the HPA axis (Lightman,
Birnie and Conway-Campbell, 2020). There is increasing evidence for an
important role of MR function in an effective neuroendocrine response,
in signaling cascades for resilience, in the development of psychiatric
disease (McEwen, Gray and Nasca, 2015) and even for brain function in
hypertensives (Brocca et al. , 2017). We did not discuss all roles
of MR – e.g., it also plays an important role in pain related pathways.
Acute antagonism of membrane bound MR on nociceptive and peripheral
neurons produces (non-genomic) antinociceptive effects (Johansson, Hao
and Sjölund, 1990; Liu et al. , 2007; Shaqura et al. ,
2016). Perhaps best studied non-genomic MR mediated effects are in the
vasculature via aldosterone activated MR pathways and, the interplay
with striatin and MR interactomes. MR-STRN3 (striatin 3) interactions
(Coutinho et al. , 2014) are possibly relevant for key cellular
processes in the brain, but regulation of brain vasculature per se may
also be relevant (Gomez-Sanchez, 2014; Ruhs et al. , 2017).
As described, complementary actions of MR and GR are predominantly
regulated by GCs, but the promiscuity of MR alludes to sex specific
responses, possibly explaining an increased incidence of depression and
anxiety in women. The antagonism of MR by its high affinity binding with
progesterone as seen from increases during the menstrual cycle or with
contraceptives, blunts MR function and causes inappropriate HPA axis
activation (Carey et al. , 1995), although most MR studies are
performed in males. With regards to circuits involved in salt seeking
behaviours, cognition and emotion, cell (and region) selective and
non-selective brain MRs, that is aldosterone and glucocorticoid
preferring cells, innervate to other physiological processes with which
the receptor is involved. Such as the aldosterone selective MR neurons
of the NTS innervating to GC preferring MRs in the forebrain and
mesolimbic cortical dopaminergic pathways of the VTA (de Kloet and
Joëls, 2017). Overall, cortisol and aldosterone mediate their effects by
targeting cell and region-specific brain MRs, and yet our understanding
of aldosterone effects in the brain remains undoubtedly hindered by
experimental challenges with the NTS and other brain regions.
Developing the molecular mechanistic underpinnings of brain MR will
further define MR biology, and its cell and context specificity requires
further teasing out of genomic interactions with its GR companion and
other TFs, coregulatory proteins, as well as rapid membrane-mediated
actions (van Weert et al. , 2017). Extensive prediction of
cell-specific MR transcriptional partners should be identified using
mass spectrometry-based approaches such as RIME (Papachristou et
al. , 2018). Likely, these interactions also depend on the specific DNA
locus (Meijer et al. , 2005; Meijer, Buurstede and Schaaf, 2019),
and this may be better understood by combining genome wide MR occupancy
with that of different coregulators. Finally, MR variants, as reported
with the haplotype 2’ (CA) mediated protective action (M D Klok et
al. , 2011; Vinkers et al. , 2015; Hamstra et al. , 2017)
and epigenetic modifications ( Martín-Blanco, A. et al., 2014)
require further attention and expansion by researchers, to delineate the
mechanisms involved in adaptation and resilience.