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Activation of estrogen-related receptor γ by calcium and cadmium

Qiaochu Wang1, Nanxi Huang2, John B Psaltis2

  • 1Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC, United States.

Frontiers in Endocrinology
|November 7, 2024
PubMed
Abstract

Insights

Calcium may be a ligand for estrogen-related receptor gamma (ERRγ), mediating glucagon's effects and cadmium's metabolic disruption. This research uncovers a novel role for calcium in metabolic regulation via ERRγ signaling.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Metabolic Regulation

Background:

  • Estrogen-related receptor gamma (ERRγ) is a key metabolic regulator.
  • The physiological ligands for ERRγ remain unidentified.
  • Understanding ERRγ's ligand interactions is crucial for metabolic control.

Purpose of the Study:

  • To investigate if calcium acts as a ligand for ERRγ.
  • To determine if calcium mediates glucagon's effects on metabolism.
  • To explore if cadmium disrupts metabolism through ERRγ.

Main Methods:

  • Cell-based assays (HepG2, MCF-7, HEK293T) with ERRγ transfection.
  • Treatments included glucagon, calcium, cadmium, ERRγ agonist, and antagonist.
  • Techniques: qPCR, Western blot, ChIP, immunofluorescence, mutational analysis, molecular dynamics simulations.

Main Results:

  • Calcium, glucagon, and cadmium induced ERRγ nuclear translocation and target gene expression.
  • ERRγ activation led to increased extracellular glucose, blocked by an ERRγ antagonist.
  • Mutational analysis identified key interaction sites (S303, T429, E452) in the ligand-binding domain.
  • Molecular dynamics simulations indicated calcium mimics ERRγ agonist effects.

Conclusions:

  • Calcium is a potential physiological ligand for ERRγ.
  • Calcium mediates glucagon-induced metabolic effects via ERRγ.
  • Cadmium disrupts cellular metabolism by acting through the ERRγ pathway.
Keywords:
cadmiumcalciumestrogen-related receptor γgluconeogenesismetals

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