Calcium-independent inhibition of glucose transport in PC-12
and L6 cells by calcium channel antagonists
Timothy D.
Ardizzone1,
Xiao-Hong
Lu1, and
Donard S.
Dwyer1,2
Departments of 1 Pharmacology and
2 Psychiatry, Louisiana State University Health
Sciences Center, Shreveport, Louisiana 71130
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ABSTRACT |
The goal of these studies was to
determine whether different calcium channel antagonists affect glucose
transport in a neuronal cell line. Rat pheochromocytoma (PC-12) cells
were treated with L-, T-, and N-type calcium channel antagonists before
measurement of accumulation of 2-[3H]deoxyglucose
(2-[3H]DG). The L-type channel antagonists
nimodipine, nifedipine, verapamil, and diltiazem all inhibited glucose
transport in a dose-dependent manner (2-150 µM) with
nimodipine being the most potent and diltiazem only moderately
inhibiting transport. T- and N-type channel antagonists had no effect
on transport. The L-type channel agonist l-BAY K 8644 also
inhibited uptake of 2-[3H]DG. The ability of these drugs
to inhibit glucose transport was significantly diminished by the
presence of unlabeled 2-DG in the uptake medium. Some experiments were
performed in the presence of EDTA (4 mM) or in uptake buffer without
calcium. The absence of calcium in the uptake medium had no effect on
inhibition of glucose transport by nimodipine or verapamil. To examine
the effects of these drugs on a cell model of a peripheral tissue, we
studied rat L6 muscle cells. The drugs inhibited glucose transport in L6 myoblasts in a dose-dependent manner that was independent of calcium
in the uptake medium. These studies suggest that the calcium channel
antagonists inhibit glucose transport in cells through mechanisms other
than the antagonism of calcium channels, perhaps by acting directly on
glucose transporters.
glucose transporter; hyperglycemia; nimodipine; verapamil
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INTRODUCTION |
GLUCOSE is the
primary energy substrate used by the adult brain (24). The
utilization of glucose by the brain is a dynamic process tightly
coupled to neuronal activity (38). How neurons regulate
glucose utilization is not known. In peripheral tissues, such as muscle
and fat, glucose transport is rate limiting for glucose utilization. In
these tissues, glucose utilization could be regulated through changes
in the number of glucose transporters (GLUTs) at the cell surface or by
changes in the intrinsic activity of GLUTs. Recently, in efforts to
study neuronal glucose metabolism, we found that many antipsychotic
drugs inhibit glucose transport in rat pheochromocytoma (PC-12) cells
(3, 11, 12). The mechanism through which these
drugs inhibit glucose uptake has not been established; however, a role
for dopamine receptors in this response has been ruled out
(11). Some of the antipsychotic drugs, the
diphenylbutylpiperidine type, are calcium channel antagonists (18), which might suggest the involvement of calcium
channels in regulation of glucose uptake. In skeletal muscle and fat,
calcium has been reported to be important for the regulation of glucose utilization. It is not known whether calcium regulates glucose transport in neurons.
Holloszy and Narahara (21) were the first to report that
calcium could mediate an increase in glucose transport in muscle tissue
preparations. Calcium has since been reported to be involved in the
modulation of glucose transport stimulated by insulin in adipocytes and
skeletal muscle (8, 26, 49). The effect of calcium channel
antagonists on glucose transport in these tissue types has been
controversial. Westfall and Sayeed (48) found that
pharmacological modulation of intracellular calcium concentrations could alter basal and insulin stimulated levels of glucose transport. Cartee et al. (7) found that L-type calcium channel
antagonists could diminish stimulation of glucose transport by insulin
in skeletal muscle while having no effect on basal transport at
concentrations that did not block calcium influx through L-type calcium
channels. The studies of Young and Balon (50) suggest that
nifedipine inhibits glucose transport through calcium-mediated effects
on the intrinsic activity of the transporter. Most of the studies involving calcium-mediated effects on glucose transport have primarily focused on compounds that affect the L-type calcium channel using peripheral tissues. The effects of the calcium channel antagonists on
glucose transport in neuronal cells have not been investigated. In this
study, we have examined the effects of antagonists of L-, T- and N-type
calcium channels on basal glucose transport in model systems of
neuronal and skeletal muscle tissues.
Calcium channel antagonists are widely used to treat a spectrum of
disease states, including hypertension (16). Most of the
drugs exert their effects through blockade of L-type calcium channels
in the vasculature to cause smooth muscle relaxation (16).
L-type channels are found in skeletal, smooth, and cardiac muscle,
endocrine cells, and neurons. Three different drug binding sites have
been identified on the L-type calcium channels: the dihydropyridine,
phenylalkylamine, and benzothiazepine binding sites
(30). L-type calcium channel antagonists have been
reported to prevent the increase in glucose transport elicited by
insulin or contraction in skeletal muscle of rats (50). In
addition, these drugs have been reported to cause profound
hyperglycemia in overdose situations (2, 20, 37) and to
exacerbate diabetic symptoms in humans (51). The
hyperglycemia in these studies has generally been attributed to the
effects of the drugs on insulin secretion (19). This study
examines the effects of the calcium channel antagonists in a model cell
culture system to determine whether these drugs modulate glucose
transport independently of their effects on insulin secretion.
In addition to L-type calcium channels, neurons also express T-
(41), P/Q- (40), R- (22), and
N-type (34) calcium channels. These channels differ in
their depolarization characteristics, function, and cellular location.
The T-type calcium channels have been therapeutically targeted for the
treatment of hypertension (45) and epilepsy
(23). The N-type calcium channels have been suggested as
possible targets for the treatment of chronic pain (4) and
traumatic brain injury (47). Other than possible effects
on insulin secretion (44), the role of these calcium channels in regulating glucose transport has not been investigated. These studies are the first to examine the possible contribution of
calcium channels to the regulation of glucose transport in neuronal cells.
For these studies, PC-12 cells were used as a neuronal cell model
system and rat L6 myoblasts were used as a model of a peripheral tissue. PC-12 cells express primarily GLUT3 at the cell surface but
also GLUT1 and GLUT3 in intracellular vesicles (28, 42). L6 myoblast cells express GLUT1, GLUT3, and very low levels of GLUT4
(6, 29); however, GLUT1 is the major isoform at the cell
surface (29). Both cell types express L-type calcium
channels (15, 33, 36). In addition, PC-12 cells also
contain N- (33) and T-type calcium channels
(15). The results of these studies demonstrate that the
calcium channel antagonists inhibit glucose transport in two different
cell types through a mechanism that is independent of these channels.
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MATERIALS AND METHODS |
Reagents and drugs.
Nifedipine, nimodipine, d-verapamil, l-verapamil,
d/l-verapamil, flunarizine, amiloride,
methoxyverapamil, nimodipine metabolite, l-BAY K 8644, d-BAY K 8644, and
-conotoxin were purchased from Research
Biochemicals International (Natick, MA). Poly-L-lysine (PLL), EDTA, and 2-deoxyglucose (2-DG) were obtained from Sigma Chemical (St. Louis, MO).
Cell lines.
PC-12 cells were obtained from American Type Culture Collection (ATCC)
and cultured in Dulbecco's modified Eagle's medium (DMEM) containing
penicillin/streptomycin, 5% fetal bovine serum, and 10% equine serum
as previously described (12, 13). L6 cells were obtained
from ATCC and cultured in DMEM containing penicillin/streptomycin and
10% fetal bovine serum according to recommended procedures.
Glucose uptake assay.
Glucose uptake was measured according to standard methods in our
laboratory (3, 11-13). Briefly, PC-12 cells (1 × 106 cells/ml) were incubated in tissue culture dishes
coated with PLL (1 mg/ml) and allowed to attach for at least 1 h.
Experiments using L6 myoblast cells were performed after overnight
incubation of 3 × 106 cells in tissue culture dishes
that were not treated with PLL. The cells were then placed in
D-glucose-free DMEM (1.5 ml) containing 25 mM
L-glucose in the presence of vehicle (DMSO), the desired drug concentrations, or 7 × 10
6 M cytochalasin B
(to account for nonspecific background by blocking transport of
glucose) for at least 15 min. 2-[3H]DG (0.5 µCi, 60 Ci/mmol; American Radiolabeled Chemicals) was added, and the dishes
were allowed to incubate at room temperature for 5 min. For some
experiments, cells were incubated with
3-O-[3H]methylglucose
(3-[3H]OMG; 2 µCi/dish, 14 Ci/mmol; Amersham,
Piscataway, NJ) for 1 min at room temperature. Uptake of the
radiolabeled glucose analogs was terminated by rapid removal of the
uptake medium followed by two washes with ice-cold PBS (pH 7.4). The
cells were lysed in 0.1% sodium dodecyl sulfate, and radioactivity was
determined in a liquid scintillation counter. To allow for comparison
between experiments, we assayed total cell protein with the Pierce BCA Kit. Within an experiment, each condition was assayed in duplicate and
each experiment was performed at least three times. Specific uptake of
the radiolabeled glucose analogs was determined by subtracting the
cytochalasin B counts from the counts obtained from the control and
test conditions. The results represent an average of at least three
experiments and are presented as the percent inhibition of glucose
uptake with drug compared with control.
Glucose sensitivity assay.
To examine whether the inhibition of glucose transport produced by
these drugs is sensitive to substrate concentrations, glucose sensitivity assays were performed as previously described
(3). Briefly, experiments were performed in the presence
(+) or absence (
) of 5 mM 2-DG. For the (+)2-DOG condition, PC-12
cells were incubated in the presence (test) or absence (control) of
drug and 5 mM 2-DG. For the (
)2-DG condition, the cells were
incubated in the presence (test) or absence (control) of drug without
2-DG. The cells were then placed in uptake medium, and the level of 2-DG (+ or
) was maintained as before. Uptake of trace amounts of
2-[3H]DG (2 µCi, 60 Ci/mmol) was measured over 5 min at
room temperature. The percent inhibition of glucose uptake was
determined by comparison of the vehicle and drug data from each
condition [(+)2-DG and (
)2-DG]. Glucose sensitivity was detected as
a change in the inhibition of glucose transport between (
)2-DG and
(+)2-DG conditions.
Calcium-independent inhibition of glucose transport.
Experiments were performed to determine whether the inhibition of
glucose transport by the drugs was mediated through the antagonism of
calcium entry into the cells. For these experiments, cells were
incubated with vehicle (control) or drug (nimodipine and verapamil for
PC-12 and nimodipine, verapamil, and diltiazem for L6) in the absence
or presence of EDTA (4 mM). Uptake of 2-[3H]DG (0.5 µCi, 60 Ci/mmol) was measured over 5 min at room temperature. To
confirm the EDTA data, we incubated PC-12 cells with vehicle (control)
or nimodipine (20 µM) in uptake buffer consisting of PBS made with or
without 0.9 mM CaCl2. The data are expressed as the percent
inhibition of glucose transport caused by the drugs compared with the
control conditions.
 |
RESULTS |
Chemical structures.
Figure 1 shows the chemical structures of
the drugs used in this study. The three classes of L-type calcium
channel antagonists are represented by nimodipine, diltiazem, and
racemic verapamil. Additional dihydropyridine compounds used in this
study include nifedipine, nifedipine metabolites, d-BAY K
8644, and the L-type agonist l-BAY K 8644. The T-type
calcium channel antagonists flunarizine and amiloride were also
examined for effects on transport. The effect on transport of the
N-type antagonist
-conotoxin was examined as well.

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Fig. 1.
Structures of the drugs used in this study. -Conotoxin
is a polypeptide with the following sequence:
CKSP*GSSCSP*TSYNCCRSCNP*YTKRCY, where P* is hydroxyproline. Nif,
nifedipine.
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Concentration-response curves.
Previous studies have shown that various antipsychotic drugs can
inhibit glucose transport in neuronal cells (11, 12). Among the most potent inhibitors were pimozide and fluphenazine, which
also block L-type calcium channels. These data suggested that drugs
which primarily block calcium channels might also affect glucose
uptake. In the present study, calcium channel antagonists were tested
for inhibition of glucose transport. PC-12 cells were allowed to attach
to tissue culture dishes coated with PLL overnight. Most drugs were
then tested for inhibition of glucose uptake over a range of
concentrations (2, 20, 40, 60, and 100 µM). Because of a lower
EC50 at the N-type calcium channels,
-conotoxin was tested at 20, 100, and 200 nM. Cells were allowed to incubate with drug
for 30 min before measurement of glucose uptake. Most of the drugs
inhibited glucose transport in PC-12 cells in a concentration-dependent manner (Fig. 2, A and
B). As determined from Fig. 2A, the
approximate IC50 of
d/l-verapamil, l-verapamil,
d-verapamil, and methoxyverapamil were 60, 75, 120, and 140 µM, respectively. The approximate IC50 values (Fig.
2B) for nimodipine, nifedipine, nifedipine metabolite, and
d-BAY K 8644 were 15, 20, 130, and 30 µM, respectively. It is noteworthy that l-BAY K 8644, a calcium channel
agonist, also inhibited uptake with an IC50 of ~70 µM.
Figure 2C shows, for comparison, the representative drugs
that bind to the three different sites on the L-type calcium channel
along with amiloride and flunarizine. Diltiazem and amiloride are weak
inhibitors of glucose transport. Flunarizine and conotoxin (Fig.
2D) did not inhibit glucose uptake at the concentrations
tested. Compounds that inhibited glucose accumulation in a
concentration-responsive manner were chosen for further
characterization.

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Fig. 2.
Dose-dependent inhibition of glucose transport. Accumulation of
3H-labeled 2-deoxyglucose (2-[3H]DG) was
measured over 5 min at room temperature in the absence or presence of
drugs indicated. A: racemic verapamil ( ),
l-verapamil ( ), d-verapamil
( ), and methoxyverapamil ( ) were
tested. B: the dihydropyridine drugs nimodipine
( ), nifedipine ( ), nifedipine
metabolite ( ), l-BAY K 8644 ( ), and d-BAY K 8644 (×) were tested.
C: dose-response curves for diltiazem ( ),
amiloride (×), and flunarizine ( ). D:
-conotoxin ( ) had no effect on glucose transport in
PC-12 cells.
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These drugs could act on the transport or the phosphorylation of 2-DG
to inhibit accumulation in cells. Immediately after transport into the
cell, 2-DG is phosphorylated by hexokinases. To rule out effects of the
drugs on hexokinase activity, we conducted some experiments
using 3-[3H]OMG, which is not phosphorylated by
hexokinases. Figure 3 demonstrates that
nimodipine and verapamil inhibit the accumulation of
3-[3H]OMG in a dose-dependent manner. This finding
suggests that the drugs inhibit the transport of glucose instead of its
metabolism.

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Fig. 3.
Dose-dependent inhibition of 3H-labeled
3-O-methylglucose (3-[3H]OMG) transport by
nimodipine and verapamil in PC-12 cells. PC12 cells were incubated with
nimodipine (open bars) or verapamil (filled bars) for 15 min before
measurement of the accumulation of 3-[3H]OMG. Data are
expressed as means ± SD of at least 3 separate
experiments.
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To examine whether the calcium channel antagonists could inhibit
glucose transport in a cell model of a peripheral tissue, we conducted
experiments in the L6 muscle cell line. L6 cells were placed in uptake
medium in the absence or presence of nimodipine, nifedipine, verapamil,
or diltiazem (2 and 100 µM for nimodipine and nifedipine and 20 and
100 µM for verapamil and diltiazem). As shown in Fig.
4, these drugs inhibited the accumulation
of 2-[3H]DG in L6 cells in a dose-dependent manner.

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Fig. 4.
Dose-dependent inhibition of glucose transport in L6
cells. L6 cells were incubated with nimodipine (Nim), nifedipine (Nif),
verapamil (Ver), and diltiazem (DTZ) for 30 min. Accumulation of
2-[3H]DG was measured over 5 min. Data are expressed as
means ± SD of 3 separate experiments.
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Time course.
The mechanism by which the drugs block glucose uptake is not known. A
drug that acts at a very early time point could directly affect the
glucose transport process. To begin to address this issue, we performed
time course experiments to determine whether the response to the drugs
had a rapid onset (Fig. 5). PC-12 cells were incubated with the various drugs (nimodipine and verapamil) for 1, 5, or 15 min before measurement of glucose transport. The drugs were
used at the 40 µM concentration. Both of the drugs inhibited the
accumulation of glucose equally at all time points, and there was no
difference between the 15- and 30-min time points in terms of
inhibition of glucose uptake. These data indicate that the drugs
achieve maximum inhibition of transport very rapidly in this system.

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Fig. 5.
Time course for the inhibition of glucose transport.
PC-12 cells were incubated with drug for 1, 5, or 15 min before
measurement of 2-[3H]DG uptake. Nimodipine and racemic
verapamil were used at 40 µM. Data are expressed as means ± SD
of 3 experiments and represent percent inhibition of glucose transport
by drugs compared with control conditions.
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Glucose sensitivity.
Cytochalasin B (5) and the atypical antipsychotic drugs
(3) have been shown to be noncompetitive antagonists of
glucose uptake into cells. To examine whether the ability of the
calcium channel drugs to inhibit glucose transport was sensitive to
glucose in the medium, we measured the uptake of trace amounts of
2-[3H]DG in the presence of drug and unlabeled 2-DG (5 mM). For comparison, the inhibition of 2-[3H]DG uptake
was determined in the presence of drug without any unlabeled glucose.
With the exception of nimodipine (40 µM), all drugs were tested at
100 µM (Fig. 6). In these experiments,
the reduction of radiolabeled substrate uptake caused by the dilution with unlabeled 2-DG was accounted for by comparing the results obtained
with the drugs to control (vehicle) data from their respective high or
low 2-DG conditions. Under these conditions the inhibitory effects of
the drugs were completely blocked in the presence of 5 mM 2-DG.

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Fig. 6.
Glucose sensitivity of drug effects. The ability of 2-DG
(5 mM) to modulate the inhibitory effects of these drugs was examined
by performing separate uptake assays in the presence or absence of
unlabeled 2-DG. For each condition (with or without 5 mM 2-DG) uptake
of trace amounts of 2-[3H]DG was measured in PC-12 cells
in the presence of vehicle (control) or drug. Nimodipine and nifedipine
were used at 20 µM, and l-verapamil was used at 40 µM.
Data are expressed as means ± SD of at least 3 separate
experiments for each condition and represent percent inhibition
produced by drugs compared with control values. These data reveal
significant (P < 0.01) attenuation of the inhibitory
effects of the drugs by 5 mM 2-DG in the uptake medium as determined by
Student's t-test.
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Calcium dependence.
The inhibition of glucose transport by l-BAY K 8644, the calcium channel agonist, and the glucose-sensitive nature of
inhibition by these drugs suggest that inhibition of transport may be
mediated through mechanisms that are independent of effects on calcium channels. To determine whether the effects of the drugs were dependent on the influx of extracellular calcium, we measured uptake of 2-[3H]DG in PC-12 cells with nimodipine (40 µM) and
verapamil (100 µM) in the absence or presence of 4 mM EDTA, a
specific calcium-chelating agent. These experiments were also
performed by using L6 cells with nimodipine, verapamil, and diltiazem
(100 µM) (Fig. 7). The presence of EDTA
in the uptake medium had no effect on the control condition or the
inhibition of transport produced by these drugs. To confirm these
findings, we performed glucose uptake assays in PC-12 cells with
nimodipine in the uptake buffer made with or without calcium. The
absence of calcium from the uptake buffer had no effect on the
inhibition of glucose transport produced by these drugs.

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Fig. 7.
Calcium-independent inhibition of glucose transport in
PC-12 and L6 cells by calcium channel antagonists. PC-12 cells
(A) were incubated with nimodipine (40 µM) and verapamil
(100 µM), and L6 cells (B) were incubated with nimodipine
(40 µM), verapamil (100 µM), and diltiazem (100 µM) for 30 min in
the absence or presence of EDTA (4 mM). C: PC-12 cells were
incubated with nimodipine (40 mM) in PBS made with or without calcium.
Accumulation of 2-[3H]DG was measured over 5 min at room
temperature. Data are expressed as means ± SD of at least 3 experiments for each condition. There are no significant differences
between the calcium and calcium-free conditions.
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 |
DISCUSSION |
Previously, the antipsychotic drugs pimozide and fluphenazine have
been shown to potently inhibit glucose transport in PC-12 cells
(11, 12). These same drugs are potent inhibitors of L-type
calcium channels (18). Therefore, it was possible that the
antipsychotic drugs might inhibit glucose transport by antagonism of
calcium channels. We (3) have recently reported that the atypical antipsychotic drugs are noncompetitive antagonists of glucose
transport in PC-12 cells, suggesting direct actions on GLUTs. However,
these findings do not preclude the involvement of calcium channels in
the regulation of glucose uptake in PC-12 cells.
Studies in muscle (48) and fat cells (43)
suggest that calcium plays a significant role in regulating glucose
utilization by altering rates of glucose transport. No previous studies
have examined the role of calcium channels in regulating glucose
transport in neurons. In this study, we examined the effects of
antagonists of L-, T-, and N-type calcium channels on glucose transport
in PC-12 and L6 myoblasts in an attempt to discern the relative
contribution of these channels to glucose transport regulation. The
findings reported here show that the L-type antagonists inhibit glucose transport into cells. A summary of various data in Table
1 reveals that there is a good
correlation between the potencies of the drugs in assays of L-type
calcium channel antagonism and their ability to block glucose
transport. On the other hand, the N- and T-type antagonists did not
inhibit glucose uptake. At first glance, these findings suggest that
the drugs may interfere with glucose transport via antagonism of L-type
channels. However, it is important to note that the drugs inhibited
calcium channels at concentrations that were about three orders of
magnitude lower than the concentrations needed to block glucose
transport. In addition, we have shown that the L-type calcium channel
agonist l-BAY K 8644 inhibited glucose uptake and that the
inhibition of transport by the drugs was sensitive to glucose in the
uptake medium. The ability of these drugs to inhibit calcium
channels is not affected by glucose. Finally, data showing that the
drugs inhibit glucose transport in the absence of calcium in the uptake buffer provide evidence that these drugs act through mechanisms other
than the inhibition of calcium channels, possibly through direct
interactions with the GLUTs.
Previous studies have shown that the increases in glucose transport
stimulated by insulin (8, 26, 49) or muscle contraction (21) are mediated by changes in intracellular calcium
levels. Calcium can come from intracellular stores or pass through the plasma membrane from the extracellular fluid through calcium channels to increase cytoplasmic calcium concentrations. Khayat et al. (25) found that the rapid increase in glucose transport
that results from mitochondrial uncoupling is dependent on calcium released from intracellular stores. On the other hand, studies with the
calcium ionophore ionomycin have demonstrated that extracellular calcium is required for insulin stimulation of glucose transport in
adipose tissue (8) and skeletal muscle (26).
Several studies have reported that agonists and antagonists of L-type
calcium channels can affect glucose transport in muscle (7, 8,
48, 50). Verapamil has been found to inhibit glucose transport
in adipose tissue (8) and skeletal muscle
(7). In addition, the dihydropyridine L-type antagonists
inhibit glucose transport in skeletal muscle (7, 48, 50).
We report here that verapamil and the dihydropyridine compounds also
inhibit glucose transport in neuronal cells, suggesting that the
mechanism for the inhibition of glucose transport by these drugs may be
similar across multiple cell types. Furthermore, our data show that, in
some cases, the calcium channel antagonists inhibit basal glucose
transport independently of their effects on calcium channels. The
calcium-independent inhibition of transport is consistent with the
observations of Cartee et al. (7) that these drugs block
glucose transport at concentrations that do not affect calcium channel
activity. These data suggest that the drugs may act directly on GLUTs.
The calcium channel antagonists have been reported to bind to many
proteins other than calcium channels. Schwartz et al. (35) reported that only a small fraction of dihydropyridine binding sites
are functional calcium channels. The dihydropyridine and phenylalkylamine drugs have been reported to bind to
-adrenergic receptors (17), P-glycoprotein (32),
1 receptors (31), the vesicular monoamine
transporter (27), and the nucleoside transporter
(39). Interestingly, binding to the nucleoside transporter was inhibited by increasing concentrations of nucleosides in the binding medium (39). We report here that increasing
concentrations of glucose in the uptake medium blocks inhibition of
glucose transport by the calcium channel antagonists. Furthermore,
these drugs inhibit glucose transport equally well in either the
absence or presence of calcium in the uptake medium. These data suggest
that GLUTs should be added to the list of proteins that bind the
dihydropyridine and phenylalkylamine drugs. In fact, we propose that
these different proteins may share common structural features to form a
promiscuous binding site such as those highlighted in a recent model of
GLUT3 that is based on an ion channel protein (9). The
summary in Table 1 supports the notion of pharmacological similarities
in the drug binding sites of GLUTs and calcium channels. The evidence for the similarities includes both the data shown here, indicating that
the drugs inhibit glucose transport and calcium channels with a similar
rank ordering, and amino acid sequence homologies between GLUTs,
calcium channels, and other transporters as reported elsewhere
(10).
The L-type calcium channel antagonists are widely prescribed for the
treatment of hypertension (16). Since the introduction of
these drugs, there have been numerous reports of hyperglycemia in
patients in overdose situations (2, 20, 37). In addition, the drugs have been reported to decrease insulin secretion in humans
(19). On the basis of this finding, the hyperglycemic effects of these drugs in humans have been have attributed to affects
on insulin secretion. Abu-Jayyab et al. (1) reported that
nifedipine-induced hyperglycemia in rats could be reversed by the
administration of metformin but not glibenclamide. Thus the
hyperglycemia may be mediated through mechanisms other than effects on
insulin secretion (1). Our data suggest that these drugs
could increase blood glucose concentrations through direct interference
with glucose uptake. Recently, we have shown that nimodipine induced
hyperglycemia in mice following acute administration of the drug
(10). Cytochalasin B produced a similar response, suggesting that antagonism of GLUTs may be partly responsible for the
hyperglycemia observed in overdose situations (10).
We are the first to report that the calcium channel antagonists can
block the transport of glucose into a neuronal cell line. In addition,
we have shown that inhibition of glucose transport by these drugs is
glucose-sensitive and independent of calcium in the uptake medium. It
would appear that the inhibition of glucose uptake is not mediated by
antagonism of calcium channels. These findings provide evidence for
some common features shared by GLUTs and calcium channels that may
suggest an evolutionary link between GLUTs, other transporters (e.g.,
the nucleoside transporter), and calcium channels proteins.
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ACKNOWLEDGEMENTS |
This work was supported by the Department of Psychiatry, Louisiana
State University Health Sciences Center, Shreveport, LA.
 |
FOOTNOTES |
Address for reprint requests and other correspondence:
D. S. Dwyer, Depts. of Pharmacology and Psychiatry, LSU
Health Sciences Center, 1501 Kings Hwy., Shreveport, LA 71130 (E-mail:
ddwyer{at}lsushc.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.
March 13, 2002;10.1152/ajpcell.00451.2001
Received 19 September 2001; accepted in final form 11 March 2002.
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