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During the past decades, the mineralocorticoid receptor (MR) has evolved from a much-overlooked member of the steroid hormone receptor family to an important player, not only in volume and electrolyte homeostasis but also in pathological changes occurring in an increasing number of tissues, especially the renal and cardiovascular systems. Simultaneously, a wealth of information about the structure, interaction partners and chromatin requirements for genomic signalling of steroid hormone receptors became available. However, much of the information for the MR has been deduced from studies of other family members and there is still a lack of knowledge about MR-specific features in ligand binding, chromatin remodelling, co-factor interactions and general MR specificity-conferring mechanisms that can completely explain the differences in pathophysiological function between MR and its closest relative, the glucocorticoid receptor. This review aims to give an overview of the current knowledge of MR structure, signalling and co-factors modulating its activity. LINKED ARTICLES: This article is part of a themed issue on Emerging Fields for Therapeutic Targeting of the Aldosterone-Mineralocorticoid Receptor Signaling Pathway. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.13/issuetoc., (© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Microglia cells are versatile players coordinating inflammatory and regenerative processes in the central nervous system in which sphingosine-1-phosphate (S1P)-mediated migration is essential. We investigated the involved signaling cascade by means of voltage clamp, measurement of ATP secretion, and wound healing assay in murine microglial BV-2 cells. S1P and extracellular hypoosmolar solution evoked an anion conductance of the cell membrane. The corresponding ion currents were inhibited by intracellular hypoosmolar solution and by the anion channel antagonists NPPB, tamoxifen, and carbenoxolone, pointing to the activation of volume-regulated anion channels (VRAC). The knockdown by siRNA indicates the involvement of LRRC8A subunits. The S1PR1-antagonist W123 and pertussis-toxin prevented the S1P-induced currents, showing the involvement of the G i -protein-coupled S1P receptor 1 (S1PR1). Furthermore, S1P and hypoosmolar extracellular solution induced an increase of ATP levels in the supernatants of BV-2 cells, which was inhibited by NPPB, tamoxifen, and W123. S1P, ATP, and ADP stimulated cell migration into the scratch area. The inhibition of S1PR1 and the downstream G i proteins hampered cell migration. Antagonists of VRAC were also able to diminish the migration of BV-2 cells. Furthermore, direct inhibition of ATP-gated P2X4 or P2X7 receptors or ADP-stimulated P2Y12 receptors blocked the stimulating effects of S1P on BV-2 cell migration. We conclude that there is an interaction between S1P receptors and purinergic receptors mediated by an S1P-induced ATP release via VRAC and that the amount of released ATP is capable of stimulating cell migration of BV-2 microglia cells via activation of P2X4, P2X7, and P2Y12 receptors., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The pathogenesis of cardiovascular diseases is a multifunctional process in which the mineralocorticoid receptor (MR), a ligand-dependent transcription factor, is involved as proven by numerous clinical studies. The development of pathophysiological MR actions depends on the existence of additional factors e.g. inflammatory cytokines and seems to involve posttranslational MR modifications e.g. phosphorylation. Casein kinase 2 (CK2) is a ubiquitously expressed multifunctional serine/threonine kinase that can be activated under inflammatory conditions as the MR. Sequence analysis and inhibitor experiments revealed that CK2 acts as a positive modulator of MR activity by facilitating MR-DNA interaction with subsequent rapid MR degradation. Peptide microarrays and site-directed mutagenesis experiments identified the highly conserved S459 as a functionally relevant CK2 phosphorylation site of the MR. Moreover, MR-CK2 protein-protein interaction mediated by HSP90 was shown by co-immunoprecipitation. During inflammation, cytokine stimulation led to a CK2-dependent increased expression of proinflammatory genes. The additional MR activation by aldosterone during cytokine stimulation augmented CK2-dependent NFκB signaling which enhanced the expression of proinflammatory genes further. Overall, in an inflammatory environment the bidirectional CK2-MR interaction aggravate the existing pathophysiological cellular situation.

The mineralocorticoid receptor (MR) belongs to the steroid receptor superfamily. Classically, it acts as a ligand-bound transcription factor in epithelial tissues, where it regulates water and electrolyte homeostasis and controls blood pressure. Additionally, the MR has been shown to elicit pathophysiological effects including inflammation, fibrosis and remodeling processes in the cardiovascular system and the kidneys and MR antagonists have proven beneficial for patients with certain cardiovascular and renal disease. The underlying molecular mechanisms that mediate MR effects have not been fully elucidated but very likely rely on interactions with other signaling pathways in addition to genomic actions at hormone response elements. In this review we will focus on interactions of MR signaling with different membrane receptors, namely receptor tyrosine kinases and the angiotensin II receptor because of their potential relevance for disease. In addition, GPR30 is discussed as a new aldosterone receptor. To gain insights into the problem why the MR only seems to mediate pathophysiological effects in the presence of additional permissive factors we will also briefly discuss factors that lead to modulation of MR activity as well. Overall, MR signaling is part of an intricate network that still needs to be investigated further., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose of the Review: The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase with a wide implication in tumor biology, wound healing and development. Besides acting as a growth factor receptor activated by ligands such as EGF, the EGFR can also be transactivated and thereby mediate cross-talk with different signaling pathways. The aim of this review is to illustrate the Janus-faced function of the EGFR in the vasculature with its relevance for vascular biology and disease., Recent Findings: Over recent years, the number of identified signaling partners of the EGFR has steadily increased, as have the biological processes in which the EGFR is thought to be involved. Recently, new models have allowed investigation of EGFR effects in vivo, shedding some light on the overall function of the EGFR in the vasculature. At the same time, EGFR inhibitors and antibodies have become increasingly established in cancer therapy, providing potential therapeutic tools for decreasing EGFR signaling., Summary: The EGFR is a versatile signaling pathway integrator associated with vascular homeostasis and disease. In addition to modulating basal vascular tone and tissue homeostasis, the EGFR also seems to be involved in proinflammatory, proliferative, migratory and remodeling processes, with enhanced deposition of extracellular matrix components, thereby promoting vascular diseases such as hypertension or atherosclerosis.

The mineralocorticoid receptor (MR), a member of the steroid receptor superfamily, regulates water-electrolyte balance and mediates pathophysiological effects in the renocardiovascular system. Previously, it was assumed that after binding aldosterone, the MR dissociates from HSP90, forms homodimers, and then translocates into the nucleus where it acts as a transcription factor (Guiochon-Mantel et al., 1989; Robertson et al., 1993; Savory et al., 2001). We found that, during aldosterone-induced nuclear translocation, MR is bound to HSP90 both in the cytosol and the nucleus. Homodimerization measured by eBRET and FRET takes place when the MR is already predominantly nuclear. In vitro binding of MR to DNA was independent of ligand but could be partially inhibited by geldanamycin. Overall, here we provide insights into classical MR signaling necessary for elucidating the mechanisms of pathophysiological MR effects and MR specificity., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objective: Pathophysiological effects of the epidermal growth factor receptor (EGFR or ErbB1) include vascular remodeling. EGFR transactivation is proposed to contribute significantly to heterologous signaling and remodeling in vascular smooth muscle cells (VSMC)., Methods and Results: We investigated the importance of EGFR in primary VSMC from aorta of mice with targeted deletion of the EGFR (EGFR(Δ/Δ VSMC)→VSMC(EGFR-/-) and EGFR(Δ/+ VSMC)→VSMC(EGFR+/-)) and the respective littermate controls (EGFR(+/+ VSMC)→VSMC(EGFR+/+)) with respect to survival, pentose phosphate pathway activity, matrix homeostasis, extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, and Ca(2+) homeostasis. In VSMC(EGFR-/-), epidermal growth factor-induced signaling was abolished; VSMC(EGFR+/-) showed an intermediate phenotype. EGFR deletion enhanced spontaneous cell death, reduced pentose phosphate pathway activity, disturbed cellular matrix homeostasis (collagen III and fibronectin), and abolished epidermal growth factor sensitivity. In VSMC(EGFR-/-) endothelin-1- or α(1)-adrenoceptor-induced ERK1/2 phosphorylation and the fraction of Ca(2+) responders were significantly reduced, whereas responsive cells showed a significantly stronger Ca(2+) signal. Oxidative stress (H(2)O(2)) induced ERK1/2 activation in VSMC(EGFR+/+) and VSMC(EGFR+/-) but not in VSMC(EGFR-/-). The Ca(2+) signal was enhanced in VSMC(EGFR-/-), similar to purinergic stimulation by ATP., Conclusions: In conclusion, EGFR was found to be important for basal VSMC homeostasis and ERK1/2 activation by the tested G-protein-coupled receptors or radical stress. Ca(2+) signaling was modulated by EGFR differentially with respect to the fraction of responders and magnitude of the signal. Thus, EGFR seems to be Janus-faced for VSMC biology.

Besides regulating water and electrolyte homeostasis, the mineralocorticoid receptor (MR) elicits pathophysiological effects in the renocardiovascular system. Although the MR's closest relative, the glucocorticoid receptor (GR), acts as a transcription factor at the same hormone-response-element (HRE), activated glucocorticoid receptor mediates very different effects. One explanation for this discrepancy is that the MR interacts with additional signaling pathways in the cytosol. In the literature, there are several indications for an interaction between aldosterone/MR and the cAMP/CREB signaling. Here we summarize the current knowledge of the cross-talk between the two signaling pathways, including some unpublished observations of our own that indicate that MR/CREB signaling is mediated by calcineurin and has potentially pathophysiological consequences., (Copyright 2009 Elsevier Inc. All rights reserved.)

Aldosterone, the endogenous ligand of the mineralocorticoid receptor (MR) in humans, is a steroid hormone that regulates salt and water homeostasis. Recently, additional pathophysiological effects in the renocardiovascular system have been identified. Besides genomic effects mediated by activated MR, rapid aldosterone actions that are independent of translation and transcription have been documented. While these nongenomic actions influence electrolyte homeostasis, pH and cell volume in classical MR target organs, they also participate in pathophysiological effects in the renocardiovascular system causing endothelial dysfunction, inflammation and remodeling. The mechanisms conveying these rapid effects consist of a multitude of signaling molecules and include a cross-talk with genomic aldosterone effects as well as with angiotensin II and epidermal growth factor receptor signaling. Rapid corticosteroid signaling via the MR has also been demonstrated in the brain. Altogether, the function of nongenomic aldosterone effects seems to be to modulate other signaling cascades, depending on the surrounding milieu.

The steroid hormone aldosterone is important for salt and water homeostasis as well as for pathological tissue modifications in the cardiovascular system and the kidney. The mechanisms of action include a classical genomic pathway, but physiological relevant nongenotropic effects have also been described. Unlike for estrogens or progesterone, the mechanisms for these nongenotropic effects are not well understood, although pharmacological studies suggest a role for the mineralocorticoid receptor (MR). Here we investigated whether the MR contributes to nongenotropic effects. After transfection with human MR, aldosterone induced a rapid and dose-dependent phosphorylation of ERK1/2 and c-Jun NH2-terminal kinase (JNK) 1/2 kinases in Chinese hamster ovary or human embryonic kidney cells, which was reduced by the MR-antagonist spironolactone and involved cSrc kinase as well as the epidermal growth factor receptor. In primary human aortic endothelial cells, similar results were obtained for ERK1/2 and JNK1/2. Inhibition of MAPK kinase (MEK) kinase but not of protein kinase C prevented the rapid action of aldosterone and also reduced aldosterone-induced transactivation, most probably due to impaired nuclear-cytoplasmic shuttling of MR. Cytosolic Ca2+ was increased by aldosterone in mock- and in human MR-transfected cells to the same extend due to Ca2+ influx, whereas dexamethasone had virtually no effect. Spironolactone did not prevent the Ca2+ response. We conclude that some nongenotropic effects of aldosterone are MR dependent and others are MR independent (e.g. Ca2+), indicating a higher degree of complexity of rapid aldosterone signaling. According to this model, we have to distinguish three aldosterone signaling pathways: 1) genomic via MR, 2) nongenotropic via MR, and 3) nongenotropic MR independent.