期刊
TOXICOLOGY AND APPLIED PHARMACOLOGY
卷 163, 期 3, 页码 260-266出版社
ACADEMIC PRESS INC
DOI: 10.1006/taap.1999.8878
关键词
lead-induced protein; lead-binding protein; GRP78; chaperones; C6 glioma cells; astroglia
资金
- NIEHS NIH HHS [R01 ES-05871, T32 ES07273, P30 ES-09106] Funding Source: Medline
Exposure to potentially neurotoxic levels of lead (Pb) occurs in about 9% of American children under 6 years of age. Astroglia in the brain serve as a Pb depot, sequestering Pb and preventing its contact with the more sensitive neurons. Astroglia have the capacity to adapt to Pb exposure, and as such are able to tolerate relatively high intracellular Pb accumulation. This tolerance mechanism has yet to be defined in biochemical terms. In the present study, we present evidence that glucose-regulated protein (GRP78), a molecular chaperone in the ER, participates directly or indirectly in the tolerance mechanism. Exposure of cultured C6 rat glioma cells, an astroglia-like cell line, to 1 mu M Pb acetate for 1 week raised the intracellular levels of two proteins, one of which was identified by sequence analysis as GRP78, GRP78 accumulation started within 1 day and progressed with time of exposure. Studies in vitro showed that GRP78 bound tightly to affinity columns with Pb2+ as the affinity ligand and bound weakly when either Zn2+ or Ni2+ replaced the Pb2+. The reduced form of GSH and BSA did not compete with GRP78 to chelate Pb2+. However, the heavy metal binding domain (HMB) of Menkes protein competed with GRP78 for chelating Pb2+. The data provide evidence that GRP78 may be a component of the Pb tolerance mechanism through its direct interaction with Pb2+. Its increased synthesis could be part of the adaptive response to Pb exposure. (C) 2000 Academic Press.
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