Abstract

Acidic microenvironment is commonly observed in tumour tissues, including glioblastoma (GBM), the most aggressive and lethal brain tumour in adults. Acid sensing ion channels (ASICs) are neuronal voltage-insensitive sodium channels, which are sensors of extracellular protons. Here we studied and functionally characterized ASICs in two primary glioblastoma stem cell lines as cell culture models. We detected transcripts of the ACCN2 and ACCN3 genes, coding for ASIC1 and ASIC3, respectively, but not transcripts of ACCN1 (coding for ASIC2). Available microarray data confirmed that ACCN1 is downregulated in glioma. Western blotting confirmed expression of ASIC1 and ASIC3, the most proton-sensitive ASICs, in both GBM cell lines. We characterized ASICs functionally using whole-cell patch clamp and detected different types of acid-sensitive currents. Some of these currents had kinetics typical for ASICs and were sensitive to specific toxin inhibitors of ASIC1a or ASIC3, demonstrating that the GBM cell lines express functional ASIC1a and ASIC3 that may enable GBM cells to sensitively detect extracellular pH in a tumour tissue. Microarray data revealed that expression of ACCN2 and ACCN3 is associated with improved survival of patients suffering from gliomas, suggesting that preserved susceptibility to extracellular pH may impair tumour growth.

Highlights

  • Glioblastoma multiforme (GBM) is the most common malignant tumour of the brain, exhibiting high rates of proliferation and infiltration

  • We show that R54 and R8 GBM stem cell (GSC) cell lines express functional ASIC1a and ASIC3 that may serve as sensitive sensors of extracellular pH, and available microarray data suggest that expression of Acid-sensing ion channels (ASICs) is associated with an improved survival

  • We examined by RT-PCR the expression of the genes that contribute to proton-gated ASICs (ASIC1a, ASIC1b, ASIC2a, ASIC2b and ASIC3) in R54 and R8 cells

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Summary

Introduction

Glioblastoma multiforme (GBM) is the most common malignant tumour of the brain, exhibiting high rates of proliferation and infiltration. They are quickly activated by acidic transients and desensitize in the continued presence of protons[7] They are expressed in virtually every neuron[6] and in some glia cells[8] and represent candidate proton sensors in GBM tissue. It has been reported that this cation conductance is due to an unconventional assembly of ASIC and epithelial sodium channel (ENaC) subunits[20] and that it regulates migration and cell cycle progression in gliomas[21]. We show that R54 and R8 GSC cell lines express functional ASIC1a and ASIC3 that may serve as sensitive sensors of extracellular pH, and available microarray data suggest that expression of ASICs is associated with an improved survival

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