30 YEARS OF THE MINERALOCORTICOID RECEPTOR: Nongenomic effects via the mineralocorticoid receptor

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   Figure 1

   Aldosterone/MR signaling. Aldosterone (aldo) has several mechanisms of action. (1) It can bind to cytosolic MR and initiate translocation of MR into the nucleus, where the MR homodimerizes and acts as a transcription factor. (2) Additionally, aldosterone and MR can initiate a crosstalk with other cytosolic signaling pathways, like for example NFAT and CREB signaling, which ultimately may affect genomic signaling. (3) Genomic MR signaling may be influenced by epigenetic regulation by histone modification or promoter methylation and also by (4) posttranscriptional regulation for example by microRNAs. (5) Aldosterone can also bind to MR attached to the plasma membrane by scaffolding proteins like Cav1 and striatin. There it may elicit nongenomic effects by interacting with receptors, i.e. receptor tyrosine kinases like EGFR, PDGFR and IGF1R or GPCR like AT1 or GPER1.
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   Figure 2

   Functional interaction between aldosterone and GPER1. There are many indications for a functional interaction between aldosterone/MR and GPER1 signaling, especially in cardiovascular cells (endothelial cells (ECs), vascular smooth muscle cells (VSMCs) and cardiomyocytes) as well as in tumor cells. NBC, sodium bicarbonate cotransporter; pMLC, phosphorylated myosin light chain.
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   Figure 3

   Components of rapid aldosterone signaling in VSMCs. Vascular smooth muscle cells (VSMCs) are one of the best studied models for nongenomic MR signaling pathways. As common interaction partners of the MR, GPCR like AT1 and GPER1 as well as receptor tyrosine kinases like EGFR, PDGFR and IGF1R have been identified at the membrane. In the cytosol, rapid MR signaling influences not only ROS homeostasis and the activity of different signaling molecules like small GTPases like RhoA and KRas but also kinases like c-src, PKC, PI3K, MAP kinases (including ERK, JNK and p38) and Ca⁺⁺ signaling.

• © 2017 Society for Endocrinology