Activation of estrogen-related receptor γ by calcium and cadmium

Objective Estrogen-related receptor gamma (ERR gamma) is a metabolic regulator with no identified physiological ligands. This study investigates whether calcium is an ERR gamma ligand that mediates the effects of glucagon and whether cadmium, which mimics the effects of calcium, disrupts metabolism through ERR gamma.Method HepG2, MCF-7, and HEK293T transfected with ERR gamma were treated with glucagon, calcium, cadmium, ERR gamma agonist, or ERR gamma inhibitor. Cells were then collected for in vitro assays including real-time qPCR, Western blot, ChIP, immunofluorescence, mutational analysis, or gene set enrichment analysis. Molecular dynamics simulations were performed to study mutation sites.Results In HepG2 cells, treatment with glucagon, calcium, or cadmium re-localized ERR gamma to the cell nucleus, recruited ERR gamma to estrogen-related response elements, induced the expression of ERR gamma-regulated genes, and increased extracellular glucose that was blocked by an ERR gamma antagonist. In MCF-7 cells and HEK293T cells transfected with ERR gamma, similar treatments induced the expression of metabolic genes. Mutational analysis identified S303, T429, and E452 in the ligand-binding domain as potential interaction sites. Molecular dynamics simulations showed that calcium induced changes in ERR gamma similar to ERR gamma agonist.Conclusion The results suggest that calcium is a potential ligand of ERR gamma that mediates the effects of glucagon and cadmium disrupts metabolism through ERR gamma.