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The Journal of Neuroscience, December 15, 1999, 19(24):10767-10777

Compromised Glutamate Transport in Human Glioma Cells: Reduction-Mislocalization of Sodium-Dependent Glutamate Transporters and Enhanced Activity of Cystine-Glutamate Exchange

Zu-Cheng Ye¹, Jeffrey D. Rothstein², and Harald Sontheimer¹

¹ Department of Neurobiology, The University of Alabama at Birmingham, Birmingham, Alabama 35294, and ² Department of Neurology, Johns Hopkins University, Baltimore, Maryland 21287

Elevated levels of extracellular glutamate ([Glu]_o) can induce seizures and cause excitotoxic neuronal cell death. This is normally prevented by astrocytic glutamate uptake. Neoplastic transformation of human astrocytes causes malignant gliomas, which are often associated with seizures and neuronal necrosis. Here, we show that Na⁺-dependent glutamate uptake in glioma cell lines derived from human tumors (STTG-1, D-54MG, D-65MG, U-373MG, U-251MG, U-138MG, and CH-235MG) is up to 100-fold lower than in astrocytes. Immunohistochemistry and subcellular fractionation show very low expression levels of the astrocytic glutamate transporter GLT-1 but normal expression levels of another glial glutamate transporter, GLAST. However, in glioma cells, essentially all GLAST protein was found in cell nuclei rather than the plasma membrane. Similarly, brain tissues from glioblastoma patients also display reduction of GLT-1 and mislocalization of GLAST. In glioma cell lines, over 50% of glutamate transport was Na⁺-independent and mediated by a cystine-glutamate exchanger (system x_c). Extracellular L-cystine dose-dependently induced glutamate release from glioma cells. Glutamate release was enhanced by extracellular glutamine and inhibited by (S)-4-carboxyphenylglycine, which blocked cystine-glutamate exchange. These data suggest that the unusual release of glutamate from glioma cells is caused by reduction-mislocalization of Na⁺-dependent glutamate transporters in conjunction with upregulation of cystine-glutamate exchange. The resulting glutamate release from glioma cells may contribute to tumor-associated necrosis and possibly to seizures in peritumoral brain tissue.

Key words: brain tumor; glutamate transporter; glutamate release; cystine-glutamate exchange; system x_c; excitotoxicity; epilepsy

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Copyright © 1999 Society for Neuroscience  0270-6474/99/192410767-11$05.00/0

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