The mineralocorticoid receptor (MR), a member of the steroid hormone receptor family, acts as an inducible transcription factor and plays an important role in water- and salt homeostasis. Additionally the activated MR induces pathophysiological changes in cardiovascular system like endothelial dysfunction, vascular remodeling and heart failure. Besides controlling gene expression (genomic MR effect), the activated MR is able to interfere with cytosolic signaling pathways (non-genomic effect) by mediation of calcineurin. Activated MR alters the subcellular distribution of PP2BA-β, enhancing its nuclear fraction, and reduces mRNA expression of the endogenous inhibitor CAIN (calcineurin inhibitor). Overall, transcriptional relevant MR/calcineurin crosstalk occurs via the catalytic subunit PP2BA-β, enables glucocorticoid response element-independent genomic signaling of MR, and is of potential pathophysiological relevance. Mechanistically, the crosstalk results from HSP90-mediated cytosolic protein complex formation, altered subcellular distribution and alter endogenous inhibitor expression.