Nuclear Shuttling Precedes Dimerization in Mineralocorticoid Receptor Signaling

SummaryThe 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 and 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.

► Translocation of MR requires aldosterone but DNA binding is aldosterone independent ► Dissociation from HSP90 leads to homodimerization of MR independent of aldosterone ► Physiological MR dimerization occurs in the nucleus ► HSP90 facilitates DNA binding of MR but not of GR