Gadolinium triggers unfolded protein responses (UPRs) in primary cultured rat cortical astrocytes via promotion of an influx of extracellular Ca2+

Cell Biol Toxicol. 2011 Feb;27(1):1-12. doi: 10.1007/s10565-010-9166-2. Epub 2010 Apr 25.


Gadolinium (Gd) and its complexes are utilized widely in industrial and clinical diagnoses. As a rare earth metal ion, free gadolinium (Gd(3+)) in the human body poses neurotoxic risks during its in vivo release and retention. In the central nervous system, astrocytes play a pivotal role in processing toxic metal ions. The present study evaluates the effects of Gd on cellular calcium homeostasis, a common mechanism that causes cell death, and on unfolded protein responses (UPRs), a mechanism for cell survival in response to toxic stimuli in mammalian cells. The experimental results indicate that the influx of extracellular Ca(2+) increases greatly after the exposure of astrocytes to Gd; however, no cell deaths were observed. Further evidence suggests the up-regulated expression of the endoplasmic reticulum (ER)-resident chaperone protein GRP78 by ER stress-mediated signal transductions, specifically the activation of ATF6, eIF2a, and IRE1. These results suggest that Gd promotes Ca(2+) influx, thus triggering UPRs, which can be closely associated to the resistance of astrocytes to Gd-induced cytotoxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Astrocytes / drug effects*
  • Astrocytes / metabolism
  • Calcium / metabolism*
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Endoplasmic Reticulum Chaperone BiP
  • Extracellular Fluid / metabolism
  • Gadolinium / toxicity*
  • Homeostasis
  • Rats
  • Rats, Sprague-Dawley
  • Unfolded Protein Response / drug effects*


  • Endoplasmic Reticulum Chaperone BiP
  • HSPA5 protein, human
  • Gadolinium
  • Calcium