title: Inhibitory regulation of glutamate aspartate transporter (GLAST) expression in astrocytes by cadmium-induced calcium influx.
abstract: After injury to the CNS, the accumulation of extracellular glutamate induces neuronal excitotoxicity, leading to secondary tissue damage. Astrocytes can reduce excess extracellular glutamate primarily through the astrocytic glutamate transporter-1 and the Na(+)-dependent glutamate/aspartate transporter (GLAST). In this study, we used an in vitro model of cadmium-induced cellular stress and found that glutamate uptake activity of astrocytes was suppressed because of cadmium-induced inhibition of GLAST expression. The blockage of cadmium-triggered Ca(2+) influx by Ca(2+) chelators elevated GLAST transcription and glutamate uptake activity in astrocytes, suggesting that the suppression of GLAST expression in cadmium-treated astrocytes was Ca(2+)-dependent. This was supported by the findings showing the reduction of GLAST mRNA in astrocytes after treatment with Ca(2+)-ionophore A23187. Cadmium reduced human GLAST promoter activity; however, it increased the binding of Ca(2+)-sensitive activator protein-1 (AP-1) and cAMP response element binding protein (CREB) to their specific elements derived from the human GLAST promoter. These results demonstrate that AP-1 and CREB may be coupled with Ca(2+)-dependent pathway triggered by cadmium to mediate the inhibition of GLAST transcription. Our results suggest that Ca(2+) influx into astrocytes after CNS injury could cause the down-regulation of GLAST expression, thus reducing the astrocytic glutamate uptake function, which in turn may exacerbate secondary damage after CNS injury.
authors: Department of Life Sciences, National Cheng Kung University, Tainan City, Taiwan.
authors: Yu-Peng
authors: YP
authors: Liu
authors: Chung-Shi
authors: CS
authors: Yang
authors: Shun-Fen
authors: SF
authors: Tzeng
mesh_terms: D027322:Amino Acid Transport System X-AG / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects*; D050882:CREB-Binding Protein / Q000378:metabolism; D019256:Cadmium Chloride / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002614:Chelating Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014162:Transfection / Q000379:methods
chemical_list: D027322:Amino Acid Transport System X-AG; D002121:Calcium Channel Blockers; D002614:Chelating Agents; D005904:Glial Fibrillary Acidic Protein; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D018698:Glutamic Acid; D050882:CREB-Binding Protein; D019256:Cadmium Chloride; D002118:Calcium