Mineralocorticoid receptor phosphorylation regulates ligand binding and renal response to volume depletion and hyperkalemia

Cell Metab. 2013 Nov 5;18(5):660-71. doi: 10.1016/j.cmet.2013.10.005.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Angiotensin II / metabolism
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Cytoplasm / drug effects
  • Cytoplasm / metabolism
  • Electrolytes / metabolism
  • Humans
  • Hyperkalemia / metabolism*
  • Hyperkalemia / physiopathology*
  • Kidney / metabolism*
  • Kidney / pathology
  • Kidney / physiopathology*
  • Ligands
  • Mice
  • Molecular Sequence Data
  • Phosphoprotein Phosphatases / metabolism
  • Phosphorylation / drug effects
  • Phosphoserine / metabolism
  • Potassium, Dietary / pharmacology
  • Protein Transport / drug effects
  • Protein-Serine-Threonine Kinases / metabolism
  • Rats
  • Receptors, Mineralocorticoid / chemistry
  • Receptors, Mineralocorticoid / genetics
  • Receptors, Mineralocorticoid / metabolism*
  • Signal Transduction / drug effects
  • Transcriptional Activation / drug effects

Substances

  • Electrolytes
  • Ligands
  • Potassium, Dietary
  • Receptors, Mineralocorticoid
  • Angiotensin II
  • Phosphoserine
  • Prkwnk4 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Phosphoprotein Phosphatases