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Chloride Accumulation Drives Volume Dynamics Underlying Cell Proliferation and Migration

Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama, Birmingham, Alabama

Submitted 31 July 2008; accepted in final form 20 November 2008

During brain development, progenitor cells migrate over long distances through narrow and tortuous extracellular spaces posing significant demands on the cell's ability to alter cell volume. This phenotype is recapitulated in primary brain tumors. We demonstrate here that volume changes occurring spontaneously in these cells are mediated by the flux of Cl^– along with obligated water across the cell membrane. To do so, glioma cells accumulate Cl^– to 100 mM, a concentration threefold greater than predicted by the Nernst equation. Shunting this gradient through the sustained opening of exogenously expressed GABA-gated Cl^– channels caused a 33% decrease in cell volume and impaired the ability of cells to migrate in a spatially constrained environment. Further, dividing cells condense their cytoplasm prior to mitosis, a phenomenon which is associated with the release of intracellular Cl^– as indicated by a 40-mM decrease in [Cl^–]_i. These findings provide a new framework for considering the role of intracellular Cl^– in glioma cells. Here, Cl^– serves as an important osmotically active regulator of cell volume being the energetic driving force for volume changes required by immature cells in cell migration and proliferation. This mechanism that was studied in CNS malignancies may be shared with other immature cells in the brain as well.