Nuclear shuttling precedes dimerization in mineralocorticoid receptor signaling.
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.
Julius-Bernstein-Institute of Physiology, University Halle-Wittenberg, Halle/Saale 06112, Germany. claudia.grossmann@medizin.uni-halle.de
Claudia
C
Grossmann
Stefanie
S
Ruhs
Lisa
L
Langenbruch
Sigrid
S
Mildenberger
Nicole
N
Strätz
Katja
K
Schumann
Michael
M
Gekle
D016227:Benzoquinones / Q000494:pharmacology; D060807:Bioluminescence Resonance Energy Transfer Techniques; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D000451:Mineralocorticoid Receptor Antagonists / Q000494:pharmacology; D055503:Protein Multimerization; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D015398:Signal Transduction; D013329:Structure-Activity Relationship
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D004247:DNA; C001277:geldanamycin