Laboratoire de Neurophysiologie, Centre National de la Recherche Scientifique UMR 5543, Université de Bordeaux 2, 33076 Bordeaux Cedex, France
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ABSTRACT |
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Our aim was to determine
whether the expression of K+ currents is related to the
cell cycle in the excitable GH3 pituitary cell line. K+
currents were studied by electrophysiology, and bromodeoxyuridine (BrdU) labeling was used to compare their expression in cells thereafter identified as being in the S or non-S phase of the cell
cycle. We show that the peak density of the transient outward K+ current (Ito) was 33% lower in
cells in S phase (BrdU+) than in cells in other phases of the cell
cycle (BrdU). The voltage-dependence of Ito
was not modified. However, of the two kinetic components of
Ito inactivation, the characteristics of the
fast component differed significantly between BrdU+ and BrdU
cells.
Recovery from inactivation of Ito showed
biexponential and monoexponential function in BrdU
and BrdU+ cells,
respectively. This suggests that the molecular basis of this current
varies during the cell cycle. We further demonstrated that
4-aminopyridine, which blocks Ito, inhibited GH3
cell proliferation without altering the membrane potential. These data
suggest that Ito may play a role in GH3 cell
proliferation processes.
potassium current; excitable cells; cell growth
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INTRODUCTION |
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A NUMBER OF RECENT STUDIES suggested that ion channels, and more particularly, K+ channels, are required for cell proliferation (9, 49). Different K+ channels have been found to be involved in the proliferation process in various cell models. Blockade of voltage-dependent K+ channels (Kv) by pharmacological agents inhibits proliferation of brown fat cells (30), myeloblastic cells (52), human melanoma cells (28, 21), prostatic cells (40), and colorectal cancer cells (53). Similarly, inhibition of ATP-sensitive or Ca2+-dependent K+ channels significantly altered the proliferation of other cell types (47, 50).
Some of these studies showed that inhibition of cell proliferation by K+ channel blockers resulted from a cell cycle block at specific phases (47, 52). More recently, the expression and/or activity of K+ channels has been found to vary according to the proliferation state of the cells or to the phases in the cell cycle. For example, in human lymphocytes, both Kv1.3 (23) and hSK4, a Ca2+/calmodulin-activated K+ channel (18), are upregulated during the proliferation process (31). Recently, Kotecha and Schlichter (19) reported that the changes in K+ currents observed during the proliferation of microglial cells corresponded to a switch in the expression of Kv1.3 and Kv1.5 channel proteins at the cell surface. In mouse oocytes, a large-conductance voltage-activated K+ channel is active throughout the M and G1 phases but inactive during the G1/S transition (8). Similarly, it seems that eag-related K+ channel regulation is cell cycle dependent in neuroblastoma cells (1). Most of those working in the field have thus suggested that these transient changes in K+ channel activity may play a key role in the transition from the quiescent state (G0) or the early G1 phase to the DNA replication (S) phase. However, despite all these studies, the link between K+ channel activity and cell cycle progression remains elusive. Among the various mechanisms proposed to account for the role of K+ channels in cell proliferation, studies have emphasized membrane hyperpolarization as an essential event required for cell cycle progression (49). According to this hypothesis, changes in membrane potential resulting from K+ channel activity directly interfere with mitogenic activity (12) and/or modify the driving force for the electrogenic transport of Ca2+ ions (4). This, in turn, would affect cell proliferation. It should be mentioned that most of these studies were performed in nonexcitable cells in which the control of membrane resting potential by K+ conductances as well as the regulation of Ca2+ influx differs drastically from that of excitable cells.
Pituitary lactotroph cells are excitable because they generate spontaneous action potentials. The ion currents expressed in this cell type have been extensively studied. However, although lactotrophs are subject to dynamic physiological (34, 38) or physiopathological (6) growth during postnatal life, the putative role of K+ channel activity in proliferation has not yet been investigated.
In recent work in the GH3 mammosomatotroph pituitary cell line, we have shown that tetraethylammonium chloride (TEA), a wide-range blocker of K+ conductances, reduced cell proliferation by inducing a cell cycle block at the G1/S transition (46). This finding suggests that K+ channels are probably involved in the proliferation of these excitable cells. The GH3 cell line expresses several K+ channels, including voltage-dependent K+ channels (29), three types of Ca2+-dependent K+ channels (10, 36), and an inward rectifying K+ channel (3). The aim of the present report was to study the expression of K+ currents in GH3 cells by using electrophysiological techniques, distinguishing between the S phase and the other cell cycle phases. We show that the density of the transient outward K+ current (Ito) drops significantly during the S phase. Moreover, inhibition of the Ito by 4-aminopyridine (4-AP) reduced cell proliferation. The involvement of this current in the electrical activity of GH3 cells was investigated and the mechanism by which Ito may play a role in cell proliferation was studied.
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MATERIALS AND METHODS |
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Cell Culture
GH3 cells were cultured in DMEM-F-12 (50:50) (Seromed, Strasbourg, France) containing 2 mM L-glutamine and 1 mM sodium pyruvate supplemented with 15% heat-inactivated horse serum (Eurobio, Les Ullis, France) and 2.5% fetal bovine serum (Seromed). The cells were routinely grown as stocks in 75-cm2 flasks (Nunc; Polylabo, Strasbourg, France) at 37°C in an humidified atmosphere (95% air-5% CO2). The medium was changed twice a week and the cells were passaged every 8-10 days.For cell proliferation assays, the cells were subcultured in 24-well plates (Nunc), seeded at 6 × 104 cells per well. For electrophysiological recordings, the cells were subcultured on microgrid glass coverslips (Eppendorf, Hamburg, Germany) pretreated with polyornithine (5 g/l). They were used 3-5 days after trypsinization.
No antibiotics were added to the cultures.
Cell Proliferation Measurement
Cell proliferation was estimated by [3H]thymidine incorporation as previously described (46). Briefly, the cells were treated for 72 h with various concentrations of 4-AP. During the last 12 h of treatment, [methyl-3H]thymidine (2 µCi/ml; ICN, Orsay, France; specific activity 60 Ci/mM) was added to the culture medium. The cultures were then washed twice in fresh culture medium and pulsed for 2 h with 5 µM unlabeled thymidine. The chase medium was discarded, and the cells were lysed in 0.2 M NaOH. After neutralization with 0.2 M HCl, the lysate was transferred into vials for scintillation counting on a Beckman LS6000 SC counter.Cytotoxicity Assays
Cell viability was determined using a Cytotoxicity Detection Kit purchased from Boehringer Mannheim (Strasbourg, France), which measures lactate dehydrogenase (LDH) activity. LDH, a stable cytosolic enzyme, is rapidly released into the culture medium after disruption of the plasma membrane. LDH activity was assessed by measuring the optical density, at 500 nm, of the cell sample medium, some of which had been treated with 4-AP.Electrophysiology
Patch-clamp recordings.
The whole cell mode of the patch technique was employed. The electrodes
were pulled on an L/U-3P (List-Medical, Darmstad, Germany) puller in
two stages from borosilicate glass capillaries (1.5-mm diameter;
Clarke, Pangbourne Readings, UK) to a tip diameter of 1.2-2 µm.
The pipette resistance was 2-4 M.
Recording solutions. The standard external solution comprised (in mM) 140 NaCl, 5 KCl, 2 CaCl2, 2 MgCl2, 0.3 Na2HPO4, 0.4 KH2PO4, 4 NaHCO3, 5 glucose, and 10 HEPES, pH 7.3 (osmolarity 300-310 mosmol/kg). Charybdotoxin (ChTX; 20 nM), tetrodotoxin (TTX; 0.5 µM), apamin (100 nM), and TEA (2 mM) were added systematically for study of the transient outward K+ current. The recording pipette was filled with a solution containing (in mM) 150 K-gluconate, 2 MgCl2, 1.1 EGTA, and 5 HEPES, pH 7.3 (osmolarity 290 mosmol/kg). GTP (40 µM) and MgATP (2 mM) were added to the pipette solution for current-clamp experiments.
An additional pipette with a tip opening of 5-10 µm was used to apply drugs by low-pressure ejection in the neighborhood of the investigated cell. All experiments were performed at 37 ± 1°C.Data analysis. In spontaneously active cells, the most hyperpolarized value measured during the first minute of recording was chosen as the membrane potential value.
Cell capacitance was measured by integrating the area of the capacitive transient elicited by a 10-mV hyperpolarizing step from the holding potential. These values were used as a measure of cell size, so voltage-clamp currents were expressed as densities (i.e., pA/pF). Normalized peak current values (I/Imax) and normalized Ito conductance (G/Gmax) were plotted against membrane potential for individual cells, and the resulting inactivation and activation curves were fitted to the Boltzmann equation: I/Imax = [1 + exp(VBrdU Labeling
We used BrdU labeling to distinguish proliferating from nonproliferating cells. BrdU was incorporated instead of thymidine into dividing cells during the S phase, without affecting the cell cycle progress. BrdU (10 µM) was added to the culture medium of GH3 cells 3 h before electrophysiological recordings were made. To prevent aspecific BrdU labeling, we added fluorodeoxyuridine (100 µM) to the external recording medium during the electrophysiological experimentation period, which lasted <1.5 h. At the end of the recording session, the cells were fixed in 70% ethanol diluted in 50 mM glycine buffer (pH 2) for at least 16 h. The incorporation of BrdU in cells was detected with a mouse anti-BrdU monoclonal primary antibody followed by an alkaline phosphatase-conjugated secondary antibody (Boehringer Mannheim). The recorded cells were located on the coverslips by their etched grid coordinates and could be identified as BrdU+ (S phase) or BrdUChemicals
ChTX was purchased from Alomone Labs (Jerusalem, Israel). Other chemicals were supplied by Sigma (L'Isle d'Abeau, Chesne, France).Statistical Analysis
Results are expressed as means ± SE. The unpaired t-test was used for statistical comparison of mean and differences, with P < 0.05 considered significant. ![]() |
RESULTS |
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To determine the putative involvement of K+ channels in GH3 cell proliferation, we compared the expression of the outward K+ currents activated by depolarization according to the cell cycle phases.
K+ Currents Elicited by Depolarization in GH3 Cells
In GH3 cells, a 100-mV depolarizing step, from a holding potential of
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Ito and
IKD Current Densities in
BrdU+ and BrdU
GH3 Cells
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Voltage Dependence of Ito in
BrdU+ and
BrdU GH3 Cells
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Ito Inactivation Kinetics in
BrdU+ and
BrdU GH3 Cells
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These data suggest that the change in Ito
current density observed between BrdU+ and BrdU cells is probably due
to a modification in the expression of the fast component of this current.
Recovery From Inactivation of Ito
The kinetics of recovery from inactivation of Ito differ markedly according to the K+ channel
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These results suggest that the molecular basis of K+
channels responsible for Ito in the S-phase
cells differs from that in the non-S phase. Ito
may be due to the activation of a single type of K+ channel
in BrdU+ cells, whereas, in BrdU cells, two types of K+
channels may be required.
Effect of K+ Channel Blocker 4-AP on [3H]Thymidine Incorporation
These results show a modification in the expression of Ito during the cell cycle. We wondered whether this modulation of Ito amplitude could be the cause or consequence of progression through the cell cycle. We therefore tested the effect of the inhibition of Ito by 4-AP on GH3 cell proliferation.Incubation of GH3 cells with increasing concentrations of 4-AP (0.1 to
0.4 mM) for 72-h induced a dose-dependent inhibition of
[3H]thymidine incorporation compared with controls (Fig.
6). This inhibition was not due to a
cytotoxic effect of 4-AP, as shown by measurement of LDH activity (Fig.
6, inset). This result suggests that
Ito current may be involved in the proliferation
process of GH3 cells.
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We then wondered whether the relationship between the variation in Ito and proliferation could be due to a modification of cell excitability.
Involvement of Ito in GH3 Cell Excitability
It has been shown that Ito is involved in the electrical activity of various cell types. We sought to determine whether the decrease in Ito amplitude observed in BrdU+ GH3 cells affected their excitability, compared with BrdU
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We then studied the effect of chronic exposure of GH3 cells to 4-AP on electrical activity. These experiments 1) investigated the role of Ito in cell excitability and 2) were intended to determine whether the effect of 4-AP on cell proliferation could be linked to putative long-term modifications in electrical activity. Cells treated for 24-30 h with 0.5 mM 4-AP showed a complete inhibition of Ito in all tested cells (n = 9), as shown by voltage-clamp experiments. In current-clamp experiments, no significant difference was observed between controls (n = 11) and 4-AP-treated cells (n = 8) in terms of membrane potential or action potential amplitude and frequency (Table 1).
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DISCUSSION |
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Until now, the involvement of K+ channels in the
control of cell proliferation had been mainly studied in nonexcitable
cell types (49). In a previous study, we showed for the
first time that K+ channels were likely to be involved in
the proliferation of excitable GH3 cells, because the broad-spectrum
K+ channel blocker TEA reduced cell proliferation by
blocking the cell cycle at the G1/S boundary
(46). In the present work, we investigated whether
K+ currents per se could be involved in the proliferation
mechanism of these excitable cells. We therefore studied the expression of K+ currents during different cell cycle phases by
combining the incorporation of BrdU and electrophysiological recordings
(see MATERIALS AND METHODS). Although the different cell
cycle phases could not be precisely distinguished with the use of this
protocol, K+ conductance expression activated by
depolarization could be easily compared in cells in the S phase (BrdU+)
and in other cell cycle phases (BrdU) without any pretreatment that
could alter cell physiology. In voltage-clamp experiments, a
depolarizing pulse from
80 to +20 mV triggered an
Ito and an IKD, which
were mainly due to voltage- and Ca2+-dependent
K+ conductances. These two currents were suppressed by the
application of 4-AP and a cocktail of K+ channel
inhibitors, TEA-ChTX-apamin, as previously described by Ritchie
(36), respectively. Comparison of both currents in BrdU+
and BrdU
cells showed a 33% lower peak density for
Ito in BrdU+ than in BrdU
GH3 cells, while the
density of IKD was unchanged. Several studies
have described modification in ion current amplitude during cell cycle
progression (1, 8, 45, 24). These changes have mainly been
observed at the G1/S and G2/M transitions. The
G1 and G2 phases of the cell cycle are the functional periods during which cells prepare for DNA replication (S
phase) and mitosis (M phase), respectively. Passage beyond the
restriction point in G1 is controlled by a number of
complex transcription factors as well as the expression of various cell cycle-related proteins. Our results suggest that changes in
Ito density between BrdU
and BrdU+ cells may
occur during the G1 or G2/M cell cycle phases.
To determine whether Ito could be involved in
proliferation processes, we then studied the effect of 4-AP on GH3 cell
proliferation. Although 4-AP is the main Ito
blocker, its inhibitory spectrum is fairly broad. To prevent possible
nonspecific effects, we used the lowest 4-AP concentrations inducing
Ito inhibition of GH3 cell proliferation. Our
results show that 4-AP inhibits GH3 cell proliferation, suggesting that
a change in Ito density may be required for cell
cycle progress. From a more physiological point of view, it is
noteworthy that thyrotropin releasing hormone, which decreases
Ito amplitude (2, 41), induces cell
cycle block in the G1 and G2/M phases in GH4
cells, a cell line closely related to GH3 (35).
Among the voltage-dependent K+ channel family (Kv), the
Shal (Kv4) and members of the Shaker (Kv1 and
particularly Kv1.4) subfamily have been shown to be responsible for
Ito in various cell types (25, 48).
The GH3 cell line expresses Kv1.4 and several types of Kv4
K+ channels, including Kv4.1 (51) and Kv4.3
(42). To determine the molecular basis for the
K+ channel(s) responsible for the
Ito expressed in BrdU+ and BrdU cells, we
studied the rate of recovery from inactivation of this current.
Recovery from inactivation revealed two kinetically distinct components
of Ito in BrdU
cells, suggesting that two
different K+ channels are responsible for this current in
S-phase cells. The kinetics of the rapid component
(
fast) were very similar to the kinetics of recovery of
Kv4 expressed in other mammalian cells (48), which
suggests that Shal-related K+ channels (i.e.,
Kv4.1 or Kv4.3) contribute to Ito in BrdU
cells. In addition to the rapidly recovering component in BrdU
cells, a slowly recovering component was also observed with a time constant that did not differ significantly from the single time constant of
BrdU+ cells. Given that Kv1.4 is expressed in GH3 cells, it is possible
that this channel contributes to Ito, although
the values of the time constants observed here (
and
slow) were faster than those usually described for Kv1.4
in mammalian cells. Kv1.4 may act as an homomeric or heteromeric
-subunit in GH3 cells along with Kv1.5 (22), and we
cannot exclude the possible participation of another K+
channel, such as Kv3.4, in Ito. Our findings
indicate that an additional Kv4 K+ channel
-subunit is
expressed or activated in BrdU
but not in BrdU+ cells. Further
molecular biology experiments will be necessary to confirm these
electrophysiological data.
In addition to recovery from inactivation, comparison of the
characteristics of Ito in BrdU+ and BrdU cells
showed a difference in inactivation kinetics of the current, whereas
activation and inactivation voltage dependencies were unchanged.
Indeed, characterization of the decaying phase of
Ito revealed that the density of the faster
component of the current (A1) was 40% higher in BrdU
than in BrdU+ cells. This was associated with an inactivation time constant (
1) faster in BrdU
than in BrdU+ cells. These
results may explain the difference in Ito
density observed between the two cell groups. Two hypotheses could
account for these results. 1) Distinct channel types mediate
the different inactivating components of the macroscopic
Ito and, by a transcriptional regulation or translocation phenomenon (27, 19), their number in the
plasma membrane may vary during the cell cycle. 2) A
posttranslational regulation of one (or more) channel types may be
responsible for the different current densities and time constants of
the decaying phase of Ito. Indeed,
Ito has been shown to be regulated by protein kinase A and/or protein kinase C in hippocampal pyramidal neurons (13) and myocytes (33). More
recently, it was found that Kv1.4 and Kv1.5 K+ channels are
regulated by tyrosine kinase phosphorylation (14, 32).
This last observation is of particular interest because tyrosine kinase
transduction pathways are involved in proliferation processes
(44).
Although the involvement of K+ channels in the proliferation of various cell types has been demonstrated, the action mechanism involved in this effect has not yet been elucidated. A number of studies have emphasized that membrane hyperpolarization is an essential event required to trigger cell proliferation (49). Membrane hyperpolarization, by increasing the driving force for Ca2+, induces a rise in intracellular Ca2+ concentration, a necessary signal for cell cycle progression (4). We wondered whether in excitable cells, in which the control of membrane potential by K+ currents and the regulation of Ca2+ homeostasis are different from those of nonexcitable cells, the coupling between the K+ conductances and the proliferation may involve a variation of membrane potential or cell excitability.
The role of Ito in cell excitability has been
extensively studied in neurons (7) and myocytes
(11), in which it is mainly involved in interspike latency
and action potential repolarization. In these cells, a variation in
Ito amplitude causes a modification in cell
excitability, which may be a messenger for cell proliferation, as
suggested for neurons during corticogenesis (26). In the present work, the fact that there is no difference between the characteristics of the electrical activity of BrdU+ and BrdU cells or
between 4-AP-treated and control cells suggests that Ito may not be involved in regulating the
excitability of GH3 cells. Although these results are surprising, they
could be explained by the biophysical characteristics of the
Ito expressed in GH3 cells. Indeed, the voltage
activation and inactivation of Ito is more
depolarized in GH3 cells than that usually described in neurons. In
neurons, the potential values for the half-inactivation and the
activation threshold are around
70 and
50 mV, respectively (39). These characteristics are compatible with a role of
Ito in the excitability of neurons (action
potential repolarization, interspike latency, and, to a lesser extent,
action potential duration) (17, 37). In GH3 cells, we
found the Ito inactivation midpoint at
40 mV
and the activation threshold at
10 mV. These results are in agreement
with those previously reported by Oxford and Wagoner (29).
However, because the electrical activity of GH3 cells is between
40
and 0 mV, these biophysical characteristics make
Ito inappropriate to play a significant role in
excitability of these cells. A transient outward K+ current
has been described in normal astrocytes but not in glioma cells. The
role of this current in nonexcitable cells of this type is not known.
However, the absence of this current in glioma cells appears to be an
early feature accompanying the transformation of a normal astrocyte
into a tumor cell (5).
However, the lack of long-term effect of 4-AP on membrane potential,
while inhibiting cell proliferation, and the absence of difference
between the membrane potential of BrdU+ and BrdU cells suggest that
variations of membrane potential are probably not involved in the
transduction pathway by which K+ channels play a role in
cell cycle progression in this cell type. Other mechanisms linking
K+ channel activity and cell proliferation have also been
proposed, including local variations in intracellular K+
concentration and/or osmolarity, which may activate several enzymes necessary for cell cycle progression (16). Another
interesting possibility is the interaction between K+
channels and oncogenes or tumor-suppressor genes. It has been shown
that transfection of fibroblasts with ras21 or treatment of
fibroblasts with growth factors leads to the induction of a Ca2+-activated K+ channel that is essential for
cell cycle progression (15). It is also noteworthy that,
in Drosophila, the product of the tumor-suppressor gene
dlg interacts with Kv1.4 K+ channels, leading to
channel clustering (43). It is clear that further
experiments will be required to determine how changes in K+
channel expression alter cell proliferation.
In conclusion, our results show that Ito is probably involved in the proliferation processes of the GH3 cell line because its inhibition by 4-AP reduces cell proliferation. Its expression level as well as its molecular composition are also clearly cell cycle dependent. Moreover, the link between Ito and cell proliferation is apparently not mediated by variations in membrane potential. It will be necessary to determine whether these findings are specific to this particular transformed cell model or whether they can be extended to other excitable pituitary and/or nonpituitary cells.
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ACKNOWLEDGEMENTS |
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This work was supported by Centre National de la Recherche Scientifique, University of Bordeaux 2, and Etablissement Public Regional Aquitaine.
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FOOTNOTES |
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Address for reprint requests and other correspondence: L. Bresson-Bepoldin, Laboratoire de Neurophysiologie, CNRS UMR 5543, Université de Bordeaux 2, 146 rue Leo Saignat, 33076 Bordeaux Cedex, France (E-mail: laurence.bepoldin{at}umr5543.u-bordeaux2.fr).
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.
Received 12 March 2000; accepted in final form 24 July 2000.
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