The mineralocorticoid receptor (MR) is a member of the nuclear receptor superfamily of transcription factors that transduces the biological effects of the corticosteroid hormone aldosterone, playing a key role in the regulation of transepithelial sodium reabsorption, extracellular volume and blood pressure. In addition, MR shows pleiotropic effects in non-epithelial tissues, affecting processes as diverse as cardiovascular homeostasis, adipocyte differentiation and function or stress responses in the hypothalamus. Antagonism of MR in humans is useful in the treatment of severe cardiac failure and some forms of hypertension. Aldosterone interaction with MR ligand binding domain (LBD) is responsible for receptor nuclear translocation, dimerization and gene transactivation. It has recently been demonstrated that phosphorylation of S843, a residue near the aldosterone binding pocket, inactivates human MR, presumably by reducing affinity for the hormone. This modification occurs in intercalated cells of the distal nephron and has been proposed to mediate selective MR activation in response to volume depletion and hyperkalemia (Shibata et al., 2013). In this work we examined the mechanisms involved in MR modulation by S843p.To that end we used mouse MR phosphomimetic mutants S839D and S839E (equivalent to S843 in human), or non-phosphorylatable mutant S839A. MR-S839D and S839E are inactive even at high aldosterone Surprisingly, aldosterone was able to induce nuclear translocation of MR-S839D and S839E, although at a slower rate than wild type receptors. Structure modeling of MR LBD and docking experiments show that S839D mutation or S839p produce the same effect, namely a small decrease in steady-state agonist docking energy. Taken together, these results suggest that the effect of S839p cannot be fully explained by decreased aldosterone binding affinity and may imply a defect in transactivation coupling. We demonstrate that uncoupling is due at least in part to decreased interaction with coactivators, such as SRC1. Co-transfection experiments showed that phosphomimicking mutant S839D significantly decreases wild type MR activity but does not affect MR dimerization. Assuming that dimerization follows a binomial distribution, our results are consistent with a dominant negative role of MR-S839D in the dimer. This has an important physiological implication, since even a low amount of MR-S839 phosphorylation would have a large impact on function.