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The Journal of Neuroscience, October 1, 2001, 21(19):7674-7683
Volume-Activated Chloride Currents Contribute to the Resting
Conductance and Invasive Migration of Human Glioma Cells
Christopher B.
Ransom,
Jeffrey T.
O'Neal, and
Harald
Sontheimer
Department of Neurobiology, University of Alabama at Birmingham,
Birmingham, Alabama 35294
We used an in vitro model for glioma cell invasion
(transwell migration assay) and patch-clamp techniques to investigate
the role of volume-activated Cl currents
(ICl,Vol) in glioma cell invasion.
Hypotonic solutions ( 230 mOsm) activated outwardly rectifying
currents that reversed near the equilibrium potential for
Cl ions (ECl).
These currents (ICl,Vol) were
sensitive to several known Cl channel inhibitors,
including DIDS, tamoxifen, and 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB). The IC50 for NPPB inhibition of
ICl,Vol was 21 µM. Under isotonic conditions, NPPB (165 µM) blocked inward
currents (at  40 mV) and increased input resistance in both standard
whole-cell recordings and amphotericin perforated-patch recordings.
Reducing [Cl]o under isotonic
conditions positively shifted the reversal potential of whole-cell
currents. These findings suggest a significant resting Cl conductance in glioma cells. Under isotonic and
hypotonic conditions, Cl channels displayed
voltage- and time-dependent inactivation and had an
I > Cl permeability. To
assess the potential role of these channels in cell migration, we
studied the chemotactic migration of glioma cells toward laminin or
vitronectin in a Boyden chamber containing transwell filters with 8 µm pores. Inhibition of ICl,Vol with NPPB
reduced chemotactic migration in a dose-dependent fashion with an
IC50 of 27 µM. Time-lapse video microscopy
during patch-clamp recordings revealed visible changes in cell shape
and/or movement that accompanied spontaneous activation of
ICl,Vol, suggesting that
ICl,Vol is activated during cell movement,
consistent with the effects of NPPB in migration assays. We propose
that ICl,Vol contributes to cell shape and
volume changes required for glioma cell migration through brain tissue.
Key words:
brain tumor; volume regulation; Cl
channels; ion channels; neuro-oncology; extracellular matrix
Copyright © 2001 Society for Neuroscience 0270-6474/01/21197674-10$05.00/0
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