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.