Mineralocorticoid receptor signaling: crosstalk with membrane receptors and other modulators.

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.

Rapid mineralocorticoid receptor trafficking.

The mineralocorticoid receptor (MR) is a ligand-dependent transcription factor that physiologically regulates water-electrolyte homeostasis and controls blood pressure. The MR can also elicit inflammatory and remodeling processes in the cardiovascular system and the kidneys, which require the presence of additional pathological factors like for example nitrosative stress. However, the underlying molecular mechanism(s) for pathophysiological MR effects remain(s) elusive. The inactive MR is located in the cytosol associated with chaperone molecules including HSP90. After ligand binding, the MR monomer rapidly translocates into the nucleus while still being associated to HSP90 and after dissociation from HSP90 binds to hormone-response-elements called glucocorticoid response elements (GREs) as a dimer. There are indications that rapid MR trafficking is modulated in the presence of high salt, oxidative or nitrosative stress, hypothetically by induction or posttranslational modifications. Additionally, glucocorticoids and the enzyme 11beta hydroxysteroid dehydrogenase may also influence MR activation. Because MR trafficking and its modulation by micro-milieu factors influence MR cellular localization, it is not only relevant for genomic but also for nongenomic MR effects.