title: Gadolinium triggers unfolded protein responses (UPRs) in primary cultured rat cortical astrocytes via promotion of an influx of extracellular Ca2+.
abstract: 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.
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, People's Republic of China.
authors.forename: Xu-Dong
authors.initials: XD
authors.lastname: Feng
authors.forename: Qing
authors.initials: Q
authors.lastname: Xia
authors.forename: Lan
authors.initials: L
authors.lastname: Yuan
authors.forename: Hai-Feng
authors.initials: HF
authors.lastname: Huang
authors.forename: Xiao-Da
authors.initials: XD
authors.lastname: Yang
authors.forename: Kui
authors.initials: K
authors.lastname: Wang
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D000091342:Endoplasmic Reticulum Chaperone BiP; D045604:Extracellular Fluid / Q000378:metabolism; D005682:Gadolinium / Q000633:toxicity*; D006706:Homeostasis; D051381:Rats; D017207:Rats, Sprague-Dawley; D056811:Unfolded Protein Response / Q000187:drug effects*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D005682:Gadolinium; D002118:Calcium