Affordable Access

deepdyve-link
Publisher Website

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

Authors
  • Shibata, Shigeru1
  • Rinehart, Jesse
  • Zhang, Junhui
  • Moeckel, Gilbert
  • Castañeda-Bueno, María
  • Stiegler, Amy L
  • Boggon, Titus J
  • Gamba, Gerardo
  • Lifton, Richard P
  • 1 Department of Genetics and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
Type
Published Article
Journal
Cell metabolism
Publication Date
Nov 05, 2013
Volume
18
Issue
5
Pages
660–671
Identifiers
DOI: 10.1016/j.cmet.2013.10.005
PMID: 24206662
Source
Medline
License
Unknown

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.

Report this publication

Statistics

Seen <100 times