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Am J Physiol Cell Physiol 293: C1181-C1185, 2007. First published July 5, 2007; doi:10.1152/ajpcell.00066.2007
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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Amiloride-sensitive Na+ channels contribute to regulatory volume increases in human glioma cells

Sandra B. Ross, Catherine M. Fuller, James K. Bubien, and Dale J. Benos

Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, Alabama

Submitted 16 February 2007 ; accepted in final form 28 June 2007

ABSTRACT

Despite intensive research, brain tumors remain among the most difficult type of malignancies to treat, due largely to their diffusely invasive nature and the associated difficulty of adequate surgical resection. To migrate through the brain parenchyma and to proliferate, glioma cells must be capable of significant changes in shape and volume. We have previously reported that glioma cells express an amiloride- and psalmotoxin-sensitive cation conductance that is not found in normal human astrocytes. In the present study, we investigated the potential role of this ion channel to mediate regulatory volume increase in glioma cells. We found that the ability of the cells to volume regulate subsequent to cell shrinkage by hyperosmolar solutions was abolished by both amiloride and psalmotoxin 1. This toxin is thought to be a specific peptide inhibitor of acid-sensing ion channel (ASIC1), a member of the Deg/ENaC superfamily of cation channels. We have previously shown this toxin to be an effective blocker of the glioma cation conductance. Our data suggest that one potential role for this conductance may be to restore cell volume during the cell's progression thorough the cell cycle and while the tumor cell migrates within the interstices of the brain.

brain tumor; sodium; epithelial sodium channel; acid-sensing ion channel; psalmotoxin

MALIGNANT GLIOMAS are derived from astrocytes and are the most common form of adult brain cancers. There is no known cure and these tumors respond poorly to current treatment modalities. Nearly 13,000 people die each year from this disease in the United States alone (9). One hallmark of malignant gliomas is their ability to invade normal brain tissue and seed new tumor growth at sites distant from the original tumor location. Several mechanisms have been implicated in glioma cell migration and invasion, e.g., enhanced expression of matrix metalloproteinase, and the anti-apoptotic protein BCL2, and upregulation of several important signaling pathways such as phosphatidylinositol-3 kinase, hypoxia-inducible factor-1, tyrosine kinases (c-Metephrin), and glial cell-derived neurotropic factor (13, 17, 18, 28, 29, 37). Several groups have hypothesized that the movement of ions through ion channels and transporters facilitate the growth and dissemination of glioma cells (4, 7, 14, 22, 24, 30, 31, 34). Specifically, glioma cells display an upregulation of chloride, potassium, sodium, and aquaporin channels not found in normal astrocytes (3, 6, 7, 12, 20, 21, 23, 25, 27, 35, 36). One such ion channel, namely, an amiloride-blockable, psalmotoxin-sensitive cation channel, has been found in human glioma cells (1, 2, 33). Its function, however, is unknown. In this study, we tested the hypothesis that this channel is important in regulatory volume increase following shrinkage of glioma cells.

MATERIALS AND METHODS

Cell culture. All experiments were performed on the glioma cell line D54-MG (glioblastoma multiforme, WHO Grade IV; Dr. Darrell Bigner, Duke University, Durham, NC). Cells were maintained in DMEM/F-12 (1:1, MediaTech) with 10% fetal calf serum (HyClone, Logan, UT), and 1% penicillin/streptomycin. Cells were cultured in a humidified incubator maintained at 37°C in a 95% O2-5% CO2 atmosphere.

Cell volume measurements. Cell volumes were measured by electronic sizing using a Coulter Counter Multisizer 3 (Beckman Coulter, Miami, FL), as previously described (4). The aperture size used in our experiments was 100 µm. Cells were detached from their culture dishes with a solution of 1 mM EDTA in phosphate-buffered Ringer solution (PBS). After the cells were pelleted by brief centrifugation, they were resuspended in Dulbecco's modified Eagle's medium (DMEM) and passed through a 40-µm nylon cell strainer. The cells were again washed, but this time they were resuspended in PBS, to which 10 mM glucose and 0.5 mM glutamine were added. This solution had an osmolality of 290 mosmol/kg. Cells were incubated for 15 min before initiating cell volume measurements. All of the volume measurements were performed at room temperature. Cell volume measurements were taken every minute over the time course of the experiment, measuring ~15,000 cells each time. A minimum of 3–5 baseline volumes were recorded before osmotic challenge. The osmolality of the bathing solution was increased by 30 mosmol/kg by the addition of NaCl or sucrose. This change in osmolality produced a modest decrease in cell volume (~5–6%) and was chosen to mimic volume changes typically seen in vivo (10, 26).

Electrophysiology. Whole cell patch-clamp recordings were performed using an Axon 200A patch-clamp amplifier. The solution compositions, voltage-clamp protocols, and data acquisition and analysis parmeters were identical to those we have previously reported (33).

Data analysis. Coulter Counter data were collected and the volume listings were exported to an Excel spreadsheet. Mean cell volumes were normalized to the average base line value for a given experiment and plotted against time. All data were plotted with the use of Origin 7.0 (Microcal, Northampton, MA) and expressed as means ± SD with the number of experiments performed under each condition in parenthesis (n). The volume regulatory portion of the generated curve was fitted visually, and the rate of volume recovery calculated from the slope (in fl/min). Significance was determined by two-tailed Student's t-test; P < 0.05 was considered significant.

RESULTS

To test the hypothesis that glioma cells can regulate their volume in response to a hyperosmotic challenge, we measured D54-MG1 cell volume using a Coulter Counter before and during exposure to hyperosmotic conditions. The cells were first suspended in isoosmotic saline and then shrunk by an average of 6% by the addition of sucrose or NaCl. Cell volumes were continuously monitored for 90–120 min. A representative experiment showing regulatory volume increase of D54-MG1 cells is shown as Fig. 1. D54-MG1 cells had an average cell volume of 3,954 fl (n = 34). Following an initial shrinkage, glioma cells recovered their volume slowly, recovering their initial volume in an average of 90 ± 8 min (n = 34; see Fig. 1A). The rate of cell volume recovery averaged 2.80 ± 0.70 fl/min. This time course of regulatory volume increase (RVI) is slower, but comparable, to the rate of regulatory volume decrease (RVD) observed following a hypoosmotic challenge (Figs. 2A, 4A, and Ref. 4).


Figure 1
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  		Fig. 1. Time course of regulatory volume increase (RVI) in D54-MG cells following osmotic shrinkage. D54-MG cells were mechanically dispersed, washed, and resuspended in PBS. At t = 2–3 min, the osmolality of the bathing medium was increased by 30 mosmol/kg by the addition of sucrose. The time course of volume recovery was continuously followed by Coulter counter analysis in the absence (control) or presence of 1 nM psalmotoxin 1 (PcTx1). Likewise, 100 µM amiloride or Na+-free solutions (iso-osmolar NMDC-CI replacements) prevented RVI. Scrambled PcTX1 peptide was used as a control and was without effect (not shown). Each trace, with the exception of A (n = 34), is representative of 4–6 separate experiments.

 

Figure 2
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  		Fig. 2. Time course of regulatory volume decrease (RVD) in D54-MG cells following osmotic swelling. The protocol followed was essentially as indicated in the legend to Fig. 1, except that at t = 0, the osmolality of the bathing medium was reduced by the addition of distilled, deionized H2O. Each trace is representative of 4–6 separate experiments.

 

Figure 4
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  		Fig. 4. Time course of RVI in the absence or presence of furosemide, EIPA, or hexamethylene amiloride (HMA) in D54-MG cells. Protocol was identical and that presented in the legend to Fig. 1. Each trace is representative of 6, 9, 6 and 3 experiments for the control, furosemide, EIPA, and HMA experiments, respectively. 1% methanol was present in all solutions.

 
Volume regulation (both RVI and RVD) in most cells has been shown to be dependent on osmolyte exchange through different pathways, e.g., ion channels or transporters. We have previously reported that glioma cells express a unique cation conductance that is not found in normal astrocytes (1, 2, 33). This conductance is blocked by the diuretic amiloride, an inhibitor of members of the ENaC/Deg superfamily of Na+ channels, and by psalmotoxin 1 (PcTx1), a specific blocker of one ENaC/Deg family member acid-sensing channel (ASIC1) (5). We therefore tested the hypothesis that RVI in glioma cells utilizes amiloride-sensitive cation channels. Under conditions of equiosmolar replacement of all of the extracellular Na+ with NMDG+, the D54-MG1 cells failed to recover their volume (n = 5) following hyperosmotic shock (Fig. 1C). Similarly, inclusion of 100 µM amiloride (Fig. 1B), or 1 nM PcTx1 (Fig. 1D) prevented RVI. In contrast, removal of extracellular Na+ or addition of amiloride or psalmotoxin had no effect on RVD in these cells (Fig. 2, B–D). Similar results were seen in SK-MG1 and U87-MG cells as well (data not shown). We do not know why D54-MG cell volume decreases below baseline in the presence of PcTX1 (Fig. 1D), but this phenomenon occurred to all of our experiments. The addition of 100 µM amiloride (Fig. 3A) or 1 nM psalmotoxin (Fig. 3B) to D54-MG cells suspended in isotonic PBS did not, by themselves, affect cellular volume at least during the first 110 min subsequent to drug addition (Fig. 3). Because removal of extracellular Na+ could decrease the activities of other ion transport systems implicated in volume responses in other cell types, we examined whether 100 µM furosemide (an inhibitor of Na-Cl–- and Na-K-CI- cotransport systems), 100 µM EIPA, and 0.5 µM hexamethylene amiloride (both inhibitors of Na+/H+ antiport) could block RVI. None of three compounds prevented RVI of D54-MG tumor cells (Fig. 4). Moreover, 0.5 µM hexamethylene amiloride was without effect on the inward Na+ currents in D54-MG cells (Fig. 5). A summary of the half-time of volume recovery D54-MG cells following shrinkage under different conditions is shown in Fig. 6.


Figure 3
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  		Fig. 3. Representation time course of D54-MG cell volume in the presence of either 100 µM amiloride (A) or 1 nM psalmotoxin (B). Experimental conditions and protocol was identical to that described in the legend to Fig. 1. These experiments were repeated 8 and 10 times with amiloride and psalmotoxin, respectively.

 

Figure 5
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  		Fig. 5. Representative whole cell current records of D54-MG cells (A) and summary current voltage (I-V) curves (B). A, left: current records from a single D54 cell before (top) and after (middle) superfusion with 100 µM amiloride. Bottom: records are the digitally subtracted currents that show the current that was inhibited by amiloride. Right: current records from a single D54 cell before (top) and after (middle) superfusion with 0.5 µM hexamethylene amiloride (HMA). The bottom record shows that after subtraction, there was no difference in the currents, indicating that the HMA failed to inhibit any whole cell current. This experiment was performed a total of 3 times for each drug treatment. Because HMA was dissolved in methanol, all solutions, including the controls, contained 1% methanol, which by itself, had no effect on whole cell currents. B: summary I–V curves of experiments presented in A. The conductance of each cell was calculated between –160 mV and the reversal potential (zero current). The mean basal conductance was 1,887 ± 1,524 pS, and the conductance in the presence of 100 µM amiloride was 1,141 ± 294 pS. A two-tailed paired t-test revealed these values to be significantly different from each other (P = 0.03). The mean conductance in the absence and presence of 0.5 µM HMA was 2,251 ± 900 and 2,265 ± 624 pS, respectively. These values are not statistically different (P = 0.97).

 

Figure 6
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  		Fig. 6. Volume recovery time following shrinkage for D-54MG glioma cells. For recovery of cell volume to 50% the time of its initial value (t1/2) was determined for each individual run and averaged. The results are expressed as mean ± 1 SD for (N) experiments under each condition. The recovery time in the presence of 100 µM furosemide was significantly different from control (P = 0.000548).

 
DISCUSSION

One hallmark of malignant brain tumors is their ability to infiltrate normal brain tissue and seed new tumors at sites considerably distant from the original location. We hypothesize that the tumor cells possess unique properties that enable this invasive potential. Recent work has provided evidence that glioma cell migration and invasion involve ion channels, specifically K+, Na+, and Cl– (4, 11, 24, 25, 30, 31, 33). Expression of these channels would thus augment the cell's ability to undergo shape and volume changes for the cell to progress through the relatively narrow extracellular spaces in the brain. Furthermore, the high rates of proliferation exhibited by glioma cells require large changes in cell volume (11).

While RVD is usually associated with cellular loss of KCl, Ernest et al. (4) concluded that both K+ (KCC1 and KCC3-) and Cl– (CLC-2, -3, -5, -6, -7) channels are involved in RVD of D54-MG glioma cells following osmotic swelling. RVI is usually associated with uptake of Na+ and sometimes other osmolytes such as inositol and taurine, from the extracellular milieu (4). It has been previously suggested that in the C6 glioma cell model, sodium uptake occurs because of the Na+/H+ exchanger (NHE) and/or the Na+-K+-CI– cotransporter (8, 15, 16, 19, 32). However, there have been few studies of RVI in human glioma cell models.

We have previously reported that cells from well-established glioma cell lines as well as those freshly dispersed from resected glioblastomas express a large cation conductance (1–3). On the basis of molecular, biochemical, and channel inhibitor studies, we have suggested that the channel underlying this conductance is composed of members of the Deg/ENaC superfamily (33). At its core is ASIC1, a member of the acid-sensitive sub-branch of the family, likely in association with ENaC subunits, thus forming a heteromeric complex. Block of this conductance is associated with a decrease in the ability of glioma cells to migrate in an in vitro assay (33). One of the key characteristics of ASIC1 is its block by the diuretic amiloride, which is a widely used inhibitor of the Deg/ENaC channel family, and its high sensitivity to the spider toxin PcTx1, which inhibits ASIC1 with nanomolar affinity. This toxin is without effect on other members of the Deg/ENaC family (tested mostly on homomeric channels), and a variety of other channels or transporters, including K+, Ca2+, and CI– channels, and NHE (5).

In the present study, we have used two blockers of ENaC/Deg, namely, amiloride and PcTx1, to determine whether the glioma cell cation conductance may contribute to volume regulation, specifically RVI, in these cells. Both compounds were found to inhibit RVI following hyperosmotic challenge at concentrations routinely used to inhibit the glioma cell cation conductance. Importantly, neither agent was an effective blocker of RVD. These data are consistent with a model in which an epithelium-like cation channel is involved in volume regulation of brain tumor cells with a highly invasive and proliferative phenotype. Thus, this cation current pathway has an essential biological function, namely, to permit a tumor cell to recover volume following its excursion through the brain parenchyma. Volume recovery is crucial for a tumor cell, because in a shrunken state, the cell cannot divide (30).

GRANTS

This work was supported by National Institutes of Health Grant CA-101952.

ACKNOWLEDGMENTS

We thank Nola Jean Ernest, Torry Tucker, and Harald Sontheimer for helpful discussions, and Erik Schwiebert for the use of the Coulter counter. We also thank Janice Phillips for excellent secretarial assistance.

FOOTNOTES


Address for reprint requests and other correspondence: D. Benos, Dept. Physiology and Biophysics, Univ. of Alabama at Birmingham, 1918 University Blvd., MCLM 704, Birmingham, AL 35294-0005 (e-mail: benos{at}uab.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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