Mineralocorticoid regulation of cell function: the role of rapid signalling and gene transcription pathways

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   Figure 1

   Overview of the cellular responses to MR activation. (A) Once activated, the mineralocorticoid receptor (MR) translocates to the nucleus and transcribes target genes including SGK1, sodium channel subunits and receptors such as the MR gene (NR3C2), epidermal growth factor receptor (EGFR), insulin-like growth factor 1 receptor (IGF1R) and angiotensin II receptor 1 (AGTR1). Some gene targets are intermediaries that activate other transcription factors. (B) Alternatively, aldosterone and MR act via second messenger systems, often by activating unrelated receptors in the absence of their ligands. Note, the MR may also signal via other MAPK cascades (JNK and p38MAPK) but only the ERK cascade is shown here. Additionally, aldosterone may act in an MR independent manner – potentially by directly binding to and activating unknown membrane receptors instead. GPER is one such proposed receptor, although MR binding to it has not been definitively demonstrated. (C) RAC1 and AGTR1 can also activate MR signalling and gene transcription in certain circumstances, in the absence of any ligand binding to MR. Some signalling pathways are redox sensitive and enabled or enhanced by NADPH oxidase (NOX) production of reactive oxygen species (ROS).
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   Figure 2

   Time course of MR effects on epithelial sodium channel (ENaC) activity in renal epithelial cells. Once activated by aldosterone, the MR triggers rapid signalling pathways, and increases transcription of intermediary genes (such as SGK1, CNKSR3 and GILZ) which enhance ENaC activity and prevent degradation, as well as direct transcription of SCNN1A which codes for the ENaC channel α-subunit. In combination, the MR can provide a rapid and sustained ENaC mediated sodium resorption in response to hypovolaemia.
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   Figure 3

   Mineralocorticoid mediated genomic (left) and non-genomic (right) events in the control of vascular function. In both endothelial (top section) and vascular smooth muscle cells (VSMCs), the PI3K pathway is an important second messenger system through which MR activates endothelial nitric oxide synthase (eNOS) and VSMC contractile elements such as myosin light chain (MLC). In VSMC, the presence of GPER enhances the effect through unknown mechanisms. Rapid effects on the ENaC sodium channel and sodium/hydrogen exchanger (NHE-1) are pro-constrictive. In VSMC, rapid increases to cAMP leads to upregulation of the CREB transcription factor, linking rapid signalling and genomic transcription. Genomic effects in endothelium includes increased synthesis of protein phosphatase 2A (PP2A) which deactivates eNOS, and NADPH oxidase (NOX) and cyclooxygenase (COX) which generate reactive oxygen species (ROS) impairing eNOS function. In VSMC, the MR can upregulate Ca_v1.2, an L-type voltage dependent calcium channel. The balance between different MR effects and other in vivo mediators determines overall vasomotor tone.

• © 2017 Society for Endocrinology