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Lead targets GRP78, a molecular chaperone, in C6 rat glioma cells
1Department of Veterinary Anatomy, Texas A&M University, College Station, Texas, 77843, USA.
Insights
Lead (Pb) exposure affects many children. Astroglia adapt by increasing glucose-regulated protein (GRP78), a molecular chaperone, which may directly bind lead, aiding tolerance.
Area of Science:
- Neuroscience
- Cell Biology
- Toxicology
Background:
- Lead (Pb) exposure is a significant public health concern, particularly for young children.
- Astroglia, a type of brain cell, sequester lead, acting as a protective depot.
- Astroglia exhibit adaptive tolerance to high intracellular lead levels, a mechanism not fully understood.
Purpose of the Study:
- To investigate the biochemical basis of astroglial lead tolerance.
- To identify specific proteins involved in the cellular adaptation to lead exposure.
- To explore the role of glucose-regulated protein (GRP78) in lead sequestration and tolerance.
Main Methods:
- Cultured C6 rat glioma cells (astroglia-like) were exposed to lead acetate.
- Intracellular protein levels were analyzed using sequence analysis.
- In vitro binding assays were performed using affinity columns with lead and other metal ions.
- Competition assays were conducted with glutathione (GSH), bovine serum albumin (BSA), and Menkes protein.
Main Results:
- Lead exposure increased intracellular levels of glucose-regulated protein (GRP78) in astroglia-like cells.
- GRP78 accumulation correlated with the duration of lead exposure.
- GRP78 demonstrated specific binding to lead ions in vitro, with weaker affinity for zinc or nickel.
- The heavy metal binding domain of Menkes protein competed with GRP78 for lead binding.
Conclusions:
- Glucose-regulated protein (GRP78) is implicated in the astroglial lead tolerance mechanism.
- GRP78 may directly interact with lead ions, facilitating cellular adaptation.
- Increased GRP78 synthesis represents a potential adaptive response to lead exposure in astroglia.
Abstract:
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 microM 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 Pb(2+) as the affinity ligand and bound weakly when either Zn(2+) or Ni(2+) replaced the Pb(2+). The reduced form of GSH and BSA did not compete with GRP78 to chelate Pb(2+). However, the heavy metal binding domain (HMB) of Menkes protein competed with GRP78 for chelating Pb(2+). The data provide evidence that GRP78 may be a component of the Pb tolerance mechanism through its direct interaction with Pb(2+). Its increased synthesis could be part of the adaptive response to Pb exposure.
