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Abstract  Two-pore domain K channels, a recently discovered family of ion channels with a unique membrane topology, have been shown to be critically involved in cell death. We here address the functional role of TASK3 (TWIK-related acid-sensitive K channel, KCNK9) in human glioblastoma in vitro and in vivo. Human glioma cell lines (n = 5) as well as glioma specimens (n = 5) constitutively express TASK3 mRNA and protein. The functional impact of the potassium channel on cell survival was investigated using a medium with high (25 mM) extracellular potassium over 7 days. Using flow cytometric assessment, we show that under these culture conditions 97 ± 0.76% of all glioma cells survived. Application of the TASK channel opener isoflurane (1 vol%) resulted in a 30 ± 4% reduction of cell survival in different glioma cell lines. Simultaneous application of isoflurane and the TASK channel blockers bupivacaine (20 μM) and spermine (500 μM) completely reversed this effect. Our results demonstrate the expression of TASK3 in glioma cells in vitro and in vivo and provide a direct link between the TASK3 channel function and glioma cell survival. This implies that TASK3 channels may possibly represent a novel molecular target for the treatment of this type of cancer. [ABSTRACT FROM AUTHOR]