The mineralocorticoid receptor (MR) forms oligomers with the heat-shock protein 
90 (Hsp90) -based heterocomplex, which contains tetratricopeptide repeat (TPR) 
domain immunophilins (IMMs). Here we investigated the unknown biological role of 
IMMs in the MR.Hsp90 complex. Upon hormone binding, FKBP52 was greatly recruited 
to MR.Hsp90 complexes along with dynein motors, whereas FKBP51 was dissociated. 
Importantly, the Hsp90 inhibitor geldanamycin impaired the retrograde transport 
of MR, suggesting that the Hsp90.IMM.dynein molecular machinery is required for 
MR movement. To elucidate the mechanism of action of MR, the synthetic ligand 
11,19-oxidoprogesterone was used as a tool. This steroid showed equivalent 
agonistic potency to natural agonists and was able to potentiate their 
mineralocorticoid action. Importantly, aldosterone binding recruited greater 
amounts of FKBP52 and dynein than 11,19-oxidoprogesterone binding to MR. 
Interestingly, 11,19-oxidoprogesterone binding also favored the selective 
recruitment of the IMM-like Ser/Thr phosphatase PP5. Each hormone/MR complex 
yielded different proteolytic peptide patterns, suggesting that MR acquires 
different conformations upon steroid binding. Also, hormone/MR complexes showed 
different nuclear translocation rates and subnuclear redistribution. All these 
observations may be related to the selective swapping of associated factors. We 
conclude that (a) the Hsp90.FKBP52.dyenin complex may be responsible for the 
retrotransport of MR; (b) a differential recruitment of TPR proteins such as 
FKBP51, FKBP52, and PP5 takes place during the early steps of hormone-dependent 
activation of the receptor; (c) importantly, this swapping of TPR proteins 
depends on the nature of the ligand; and (d) inasmuch as FKBP51 also showed an 
inhibitory effect on MR-dependent transcription, it should be dissociated from 
the MR.Hsp90 complex to positively regulate the mineralocorticoid effect.