title: Mineralocorticoid receptor phosphorylation regulates ligand binding and renal response to volume depletion and hyperkalemia.
abstract: Nuclear receptors are transcription factors that regulate diverse cellular processes. In canonical activation, ligand availability is sufficient to produce receptor binding, entraining downstream signaling. The mineralocorticoid receptor (MR) is normally activated by aldosterone, which is produced in both volume depletion and hyperkalemia, states that require different homeostatic responses. We report phosphorylation at S843 in the MR ligand-binding domain that prevents ligand binding and activation. In kidney, MR(S843-P) is found exclusively in intercalated cells of the distal nephron. In volume depletion, angiotensin II and WNK4 signaling decrease MR(S843-P) levels, whereas hyperkalemia increases MR(S843-P). Dephosphorylation of MR(S843-P) results in aldosterone-dependent increases of the intercalated cell apical proton pump and Cl(-)/HCO3(-) exchangers, increasing Cl(-) reabsorption and promoting increased plasma volume while inhibiting K(+) secretion. These findings reveal a mechanism regulating nuclear hormone receptor activity and implicate selective MR activation in intercalated cells in the distinct adaptive responses to volume depletion and hyperkalemia.
authors.affiliation: Department of Genetics and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Shibata
authors.forename: Jesse
authors.initials: J
authors.lastname: Rinehart
authors.forename: Junhui
authors.initials: J
authors.lastname: Zhang
authors.forename: Gilbert
authors.initials: G
authors.lastname: Moeckel
authors.forename: María
authors.initials: M
authors.lastname: Castañeda-Bueno
authors.forename: Amy L
authors.initials: AL
authors.lastname: Stiegler
authors.forename: Titus J
authors.initials: TJ
authors.lastname: Boggon
authors.forename: Gerardo
authors.initials: G
authors.lastname: Gamba
authors.forename: Richard P
authors.initials: RP
authors.lastname: Lifton
mesh_terms: D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004573:Electrolytes / Q000378:metabolism; D006801:Humans; D006947:Hyperkalemia / Q000378:metabolism* / Q000503:physiopathology*; D007668:Kidney / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D017419:Potassium, Dietary / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D018161:Receptors, Mineralocorticoid / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D004573:Electrolytes; D008024:Ligands; D017419:Potassium, Dietary; D018161:Receptors, Mineralocorticoid; D000804:Angiotensin II; D010768:Phosphoserine; C499024:Prkwnk4 protein, mouse; D017346:Protein Serine-Threonine Kinases; D010749:Phosphoprotein Phosphatases