Abteilung Klinische Biochemie, Zentrum Innere Medizin, University of Göttingen, 37075 Göttingen, Germany
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ABSTRACT |
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Calcium entry in nonexcitable cells occurs through Ca2+-selective channels activated secondarily to store depletion and/or through receptor- or second messenger-operated channels. In amphibian liver, hormones that stimulate the production of adenosine 3',5'-cyclic monophosphate (cAMP) also regulate the opening of an ion gate in the plasma membrane, which allows a noncapacitative inflow of Ca2+. To characterize this Ca2+ channel, we studied the effects of inhibitors of voltage-dependent Ca2+ channels and of nonselective cation channels on 8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP)-dependent Ca2+ entry in single axolotl hepatocytes. Ca2+ entry provoked by 8-BrcAMP in the presence of physiological Ca2+ followed first-order kinetics (apparent Michaelis constant = 43 µM at the cell surface). Maximal values of cytosolic Ca2+ (increment ~300%) were reached within 15 s, and the effect was transient (half time of 56 s). We report a strong inhibition of cAMP-dependent Ca2+ entry by nifedipine [half-maximal inhibitory concentration (IC50) = 0.8 µM], by verapamil (IC50 = 22 µM), and by SK&F-96365 (IC50 = 1.8 µM). Depolarizing concentrations of K+ were without effect. Gadolinium and the anti-inflammatory compound niflumate, both inhibitors of nonselective cation channels, suppressed Ca2+ influx. This "profile" indicates a novel mechanism of Ca2+ entry in nonexcitable cells.
adenosine 3',5'-cyclic monophosphate; second messenger-operated calcium channel; calcium channel pharmacology; SK&F-96365; fenamates
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INTRODUCTION |
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THE REGULATION OF GLYCOGEN breakdown in mammalian liver
by -adrenergic agonists and vasoactive peptides has been extensively studied. These hormones generate as second messengers diacylglycerol and inositol 1,4,5-trisphosphate
(InsP3); the latter mobilizes Ca2+ from the endoplasmic
reticulum and in addition triggers
Ca2+ entry into the cell (5). In
most cells, including hepatocytes (18, 22, 26), the rate of
Ca2+ influx after hormonal
stimulation seems to be controlled by the filling state of internal
InsP3-sensitive
Ca2+ stores (34). When such stores
are depleted, an inflow of Ca2+ is
triggered by a mechanism that may depend on the presence of Ca2+,
InsP3, and/or inositol
1,3,4,5-tetrakisphosphate, or other yet to be defined diffusible
factors (reviewed in Ref. 6). In rat liver, the rate of
Ca2+ entry into cells via
store-operated channels may be enhanced if glucagon or other adenosine
3',5'-cyclic monophosphate (cAMP)-generating hormones are
present during a challenge with
Ca2+-dependent hormones (7, 28).
The nature of this mechanism is obscure at the present.
Very recently, investigations on Drosophila melanogaster have drawn attention to certain proteins (trp, trpl) with an apparent capacity of both channel forming and the sensing of the filling state of the endoplasmic reticulum Ca2+ store (32, 33). Hence, the Drosophila store-operated channel has been put forward as a model for capacitative Ca2+ entry. Analogous proteins, however, have not been detected in liver (43).
In variance, in fish and amphibian liver, the effect of adrenergic
agonists and vasotocin is mediated via the generation of cAMP (19, 20,
42), and not via InsP3. Yet, in
parenchymal liver cells from axolotl (Ambystoma
mexicanum), hormones that stimulated cAMP
formation (the order of efficacy was glucagon > isoprenaline > epinephrine arginine vasotocin)
also provoked a pronounced increase in cytosolic
Ca2+, which was not due to a
mobilization of the cation from internal stores by
InsP3/thapsigargin, but to an
increased inflow from the extracellular medium. Thus, in axolotl liver,
in contrast to rat liver, hormones that stimulate the production of
cAMP also regulate the opening of an ion gate in the plasma membrane,
which allows an inflow of Ca2+
(and Mn2+). The effect is rather
specific, since guanosine 3',5'-cyclic monophosphate (cGMP)
failed to induce Ca2+ entry (23).
We have proposed that this channel could belong to the category of
second messenger-operated Ca2+
channels, as defined by Meldolesi and Pozzan (29). In nonexcitable tissues, such channels have so far only been found in blood cells (10,
27, 36).
The aim of this investigation was to further characterize the nature of
this cAMP-activated Ca2+ channel
of axolotl liver cells, using a variety of compounds that influence
Ca2+ entry in excitable and
nonexcitable cells: the phenylalkylamine verapamil, the dihydropyridine
nifedipine, both potent inhibitors of
Ca2+ entry in heart and skeletal
muscle, and the imidazole derivative SK&F-96365, which inhibited
receptor-mediated Ca2+ entry (as
compared with receptor-mediated
Ca2+ release) in nonexcitable
cells (human platelets, neutrophils, and endothelial cells) and which
has been used as a tool to discriminate between voltage-gated
Ca2+ entry and receptor-mediated
Ca2+ entry in
GH3 and artery smooth muscle cells
(30). Because lanthanides (107 to
10
5 M) block stretch- and
receptor-activated nonselective cation channels, but also
Ca2+ entry through
voltage-dependent channels (15), we investigated the effect of
Gd3+ on cAMP-dependent
Ca2+ entry. As an additional
inhibitor of nonselectivc cation channels in membranes, we examined the
effect of niflumate, a nonsteroidal anti-inflammatory drug (12, 15).
Using single-cell dual-wavelength epifluorescence measurements of
cytosolic Ca2+ in amphibian
hepatocytes, we report a strong inhibition of cAMP-dependent Ca2+ entry by SK&F-96365
[half-maximal inhibition concentration
(IC50) = 1.8 × 106 M], by the
dihydropyridine nifedipine (IC50 = 8 × 10
7 M), and by
verapamil. Furthermore, the lanthanide
Gd3+ and niflumate, both potent
inhibitors of nonselective cation channels, suppressed
Ca2+ influx. It is concluded that
in axolotl hepatocytes the rise in intracellular
Ca2+ after hormonal stimulation is
due to a Ca2+ inflow via a novel
dihydropyridine- and SK&F-96365-sensitive nonselective cation channel.
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MATERIALS AND METHODS |
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Materials.
Fura 2 acetoxymethyl ester (AM) was purchased from Molecular Probes
(Eugene, OR). SK&F-96365
{1-(-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl)-1H-imidazole hydrochloride} was a kind gift from SmithKline Beecham
Pharmaceuticals (Welwyn, UK). BAY K 8644 was from Bayer. Collagenase
("Worthington" type CLS II, 206 U/mg) came from Biochrom (Berlin,
Germany). 3-Aminobenzoic acid ethyl ester (MS-222) was from Sigma
(Munich, Germany). All other chemicals were of analytical grade and
were obtained from Merck (Darmstadt, Germany).
Isolation of hepatocytes. Axolotls (A. mexicanum) were maintained in aerated water tanks at 20°C. The animals were fed twice weekly on fish pellets (Fisch-Fit, Interquell Stärke, Wehringen, Germany) and had a body weight of 60-80 g when used. Results from both males and females are presented together, because there were no differences observed between sexes (19).
The animals were anesthetized by immersion in 0.05% (wt /vol) MS-222. The cannulation and extirpation of the liver were as described previously (19, 23). Hepatocytes were prepared using Ca2+-free amphibian Krebs-Ringer bicarbonate buffer (aKRB) (80 mM NaCl, 3 mM KCl, 0.6 mM KH2PO4, 0.8 mM MgSO4, and 16 mM NaHCO3, pH 7.4) as the perfusate. Briefly, the liver was perfused via the portal vein for 15 min with the above medium in an open perfusion, and then after readdition of CaCl2 (1 mM) and collagenase (0.05 g/100 ml), the perfusion was continued for 40-50 min in a recirculating system. After this step, the liver was minced, and the disintegrating tissue fragments as well as separated single cells were collected and passed through a double layer of cheesecloth. This suspension was washed three times with aKRB by centrifugation (100 g for 1 min). Usually >85% of the cells were viable as judged by trypan blue exclusion (0.2% trypan blue, 1% bovine serum albumin in aKRB).Measurement of cytosolic Ca2+. The cells were washed once (100 g for 1 min) and resuspended in a medium containing 80 mM NaCl, 3.2 mM KCl, 0.8 mM MgSO4, 1 mM CaCl2, 10 mM D-glucose, and 20 mM N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid, pH 7.4 (medium A) to give a concentration of ~60 mg wet wt /ml. They were incubated with fura 2-AM (5 µM) for 30 min at 25°C in a shaking water bath (100 cycles/min). After this, the cells were spun down (1 min, 100 g), the supernatant was discarded, and the pellet was resuspended in the same volume of medium A and further incubated for up to 30 min at 4°C. Thereafter, the cells were washed twice with medium A (100 g, 1 min) and resuspended in medium A at a concentration of 80-100 mg wet wt /ml. This suspension was kept for up to 30 min at room temperature to allow deesterification of fura 2-AM. The latter was controlled during this period by monitoring the epifluorescence of single hepatocytes at 360-nm excitation. Ca2+ concentration was calculated from the fluorescence ratio 360/380 nm (31). Hepatocytes (1-2 mg wet wt) were suspended in 2 ml medium A (plus additions as specified) in a petri dish (Falcon 3001) with a central quartz window (diameter = 15 mm). Water-insoluble compounds were prepared as concentrated stock solutions in dimethyl sulfoxide (DMSO). The concentration of DMSO in the petri dish never exceeded 1% (vol/vol). The same amount of DMSO was added to control incubations.
Ca2+ measurements were performed on single hepatocytes using a fura 2 data aquisition system (Luigs and Neumann, Ratingen, Germany) mounted to an inverted microscope (Zeiss IM 35) equipped with epifluorescence, a xenon lamp (Osram, XBO 75 W/2), a rotating filter wheel (357/380- to 390-nm excitation, 480- to 540-nm emission), and a photomultiplier (Hamamatsu 928 SF). The sampling rate was 2/s. For a more detailed description and evaluation of the equipment, see Neher (31). Calibration of the system was done using fluorescent beads.Application of agonists. Application of agonist [8-bromoadenosine 3',5'-cyclic monophosphate (8-BrcAMP)] was done using a microcapillary to direct a flow of solution of agonist under constant pressure (1,000 hPa) from a distance of ~30 µm for 5-10 s onto the equatorial surface of the single cell under investigation. The capillary (2-3 µm diameter) was positioned using an Eppendorf ECET 5170 micromanipulator, and an ECET microinjection system (Eppendorf 5242) coupled to the capillary was activated for the time and pressure specified to generate the flow of agonist. All other compounds were dissolved in medium A and were present in the "bath" (petri dish) at concentrations given in Figs. 1-5.
The rate of Ca2+ increase (nM/s) and the maximum level in cytosolic Ca2+ ( ![]() |
RESULTS |
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Kinetics of cAMP-dependent
Ca2+ uptake.
8-BrcAMP (1 mM) when applied from the outside using a microinjection
glass capillary for 5 s from a distance of ~30 µm onto the surface
of single axolotl hepatocyte led after a short delay to an increased
influx of Ca2+, as shown for six
of seven individual hepatocytes in the same petri dish (Fig.
1). In most cells, the increase of
cytosolic Ca2+ was transient with
a half-life of decay of ~1 min (57 ± 4 s, n = 6). Some cells
however exhibited longer-lasting responses, some also with superimposed
oscillations (not shown). Maximum levels of cytosolic
Ca2+
(Ca2+: 211 ± 20 nM;
n = 5) were obtained within 15 s
(rate: 13 ± 1.5 nM/s; n = 6).
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Effect of SK&F-96365 on cAMP-dependent
Ca2+ entry.
The imidazole derivative SK&F-96365 has been introduced as a tool to
discriminate between voltage-gated
Ca2+ entry and receptor-mediated
Ca2+ entry (30). SK&F-96365
inhibited cAMP-dependent Ca2+
inflow in axolotl hepatocytes in a dose-dependent manner. The dose-response curves for the rate of
Ca2+ entry and for the maximal
increase are shown in Fig. 3. The
IC50 values for SK&F-96365 were
1.4 and 1.7 × 106 M
for the rate of Ca2+ entry and
maximal increase (
Ca2+),
respectively.
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Effect of dihydropyridines and verapamil on cAMP-dependent
Ca2+ entry.
The dihydropyridine (8, 9) nifedipine, when tested under comparable
conditions, inhibited markedly the cAMP-dependent Ca2+ influx
(IC50 = 8 × 107 M). This sensitivity is
20-50 times more pronounced than that reported for liver by others
(18, 26). BAY K 8644, an agonistic dihydropyridine, which binds during
the open state of L-type Ca2+
channel and prolong their open time (24), when present in equimolar concentration had no additional effect (Fig.
4A,
open square). BAY K 8644 at 2.5 µM on its own, however, increased the
basal Ca2+ by 17% and cAMP (1 mM)-dependent
Ca2+ by 47%.
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Effect of
Gd3+ on
cAMP-dependent
Ca2+ entry.
The lanthanide Gd3+ inhibited
cAMP-dependent Ca2+ entry very
efficiently. A 50% inhibition of the rate of
Ca2+ entry and of the maximal
increase of cytosolic Ca2+ was
observed at a concentrations of 2.5 × 106 M (Fig.
5).
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Effect of niflumate on cAMP-dependent
Ca2+ entry.
Niflumate inhibited cAMP-dependent
Ca2+ entry by ~90% (rate: 9.6 and 7.2%; Ca2+: 13.6 and
13.2% of control at 1 or 5 × 10
4 M niflumate,
respectively).
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DISCUSSION |
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Using dual-wavelength excitation epifluorescence measurements of Ca2+ on single hepatocytes, we demonstrate here unique properties of this Ca2+-conducting channel in axolotl hepatocytes (a nonexcitable splanchnic cell).
The entry of Ca2+ evoked by cAMP
was strongly inhibited by the imidazole derivative SK&F-96365
(IC50 ~2 × 106 M), whereas that after
microinjection of InsP3 was
inhibited only at concentrations
>10
4 M (data not shown).
This inhibition is about one order of magnitude more effective than
that described for a variety of different cells including rat
hepatocytes (0.8-3 × 10
5 M, see Refs. 10, 11,
25, 30, 40). SK&F-96365, which belongs to a group of imidazole
antimycotics that have been originally used to block cytochrome
P-450 but also
Ca2+ and
Ca2+-dependent
K+ channels (3), was introduced as
a novel inhibitor of receptor-mediated Ca2+ entry into cells (30). In
addition, inhibition of voltage-gated Ca2+ entry in
GH3 and rabbit ear artery smooth
muscle cells by SK&F-96365 has been observed (30). The mechanism of
this inhibition is still elusive. The proposal, however, that
cytochrome P-450 may link
intracellular Ca2+ stores with
plasma membrane influx (2) has been questioned by others (36). In
axolotl liver, we could exclude a participation of intracellular,
capacitative stores in cAMP-dependent
Ca2+ influx, which is in support
of a cytochrome P-450-independent interaction (23).
Opposing effects of SK&F-96365 on HL-60 cells have been recently reported by Leung et al. (25). At low concentrations (<16 µM), SK&F-96365 inhibited Ca2+ entry, whereas at higher concentrations (16-100 µM), it provoked release of intracellular Ca2+, and by this promoted even Ca2+ entry (30-100 µM). The latter could be inhibited by La3+, but not by nifedipine.
The comparably sensitive inhibition of cAMP-dependent
Ca2+ entry observed in the
presence of the dihydropyridine derivative nifedipine was not expected.
Dihydropyridines are known to block rather selectively L-type
voltage-dependent Ca2+ channels of
excitable tissues (9), a channel type which is absent in hepatocytes,
as judged by electrophysiological measurements (37) or Northern
analysis (17). This is confirmed by our failure to demonstrate
Ca2+ entry after membrane
depolarization in the presence of
K+ (100 mM), which reveals that
the channel decribed here although sensitive to dihydropyridines lacks
certain properties of a classical L-type channel of excitable cells, in
particular, the ability of voltage sensing, a property which is
thought to be located on the S4 segment of the
1-subunit
(9).
Ca2+ influx channels of
nonexcitable cells sharing these properties have been recently found in
B lymphocytes from rat, which showed dihydropyridine but no voltage
sensitivity (1), and in an erythroleukemia cell line from mouse, where
a truncated 1-subunit lacking
the first four transmembrane segments was expressed (27). Furthermore,
the
trp/trpl
gene product from Drosophila that
forms a nonselective cation channel presumably involved in capacitative
Ca2+ entry in invertebrates and
vertebrates shows some sequence homology to the voltage-operated
Ca2+ channel
1-subunit, but lacks arginine
residues of the S4 region (33, 41).
The phenylalkylamine verapamil inhibited Ca2+ entry in axolotl hepatocytes (50% effective concentration = 22 µM) but in comparison with nifedipine with lower sensitivity. In contrast to dihydropyridines, phenylalkylamines enter the cell to interact with a high-affinity binding protein on the endoplasmic reticulum, which has been identified in guinea pig and human liver (14). As for nifedipine, the effects of verapamil reported so far for liver (and hepatocytes) are rather controversial. Studying capacitative Ca2+ entry, Llopis et al. (26) failed to see effects of verapamil or nifedipine (up to 50 µM), whereas Striggow and Bohnensack (38) observed an incomplete inhibition of this Ca2+ entry mechanism at verapamil or diltiazem concentrations between 200 and 400 µM. Others have reported complete inhibition of 45Ca2+ exchange across the liver cell plasma membrane in the presence of 50-100 µM nifedipine or verapamil (18). A stretch-activated nonselective cation channel found in rat hepatocytes and rat hepatoma cells was not affected by nifedipine, verapamil, or La3+ (4).
The effect of nifedipine (or verapamil) shown here on axolotl hepatocytes appears to be more specific, since the effective concentration of nifedipine (1-5 µM) is the order of magnitude used to block voltage-dependent L-type Ca2+ channels of excitable cells in vitro, i.e., 1-10 µM.
The inhibition of cAMP-dependent Ca2+ entry observed in axolotl hepatocytes in the presence of niflumate or the lanthanide Gd3+ was not surprising. Both compounds are potent inhibitors of Ca2+ entry through nonselective cation channels (Ref. 15 and references therein). Because of an ionic radius close to that of Na+ and Ca2+, Gd3+ (0.2-100 µM) can block efficiently stretch- or receptor-activated nonselective cation channels (4, 11, 40) but, like La3+, also voltage-dependent channels (39).
The nonsteroidal anti-inflammatory fenamates have been applied to block
Ca2+ entry via nonselective cation
channels in cells from rat exocrine pancreas (12), in human polynuclear
leukocytes (21), and in mucosa-type mast cells (35). Apart from
nonselective cation channels,
Cl channels are blocked by
fenamates (13, 35). In mucosa-type mast cells, the
Cl
channel blocker
4,4'-diisothiocyanostilbene-2,2'-disulfonic acid, however,
fully obstructed Cl
currents without affecting Ca2+
influx, thus indicating that the effect of niflumate on
Ca2+ influx may be dissociated
from that on Cl
channels
(35).
As discussed above, all compounds used here, except for nifedipine and verapamil, are to a variable degree inhibitory on capacitative Ca2+ entry (11, 16, 21, 25, 26, 40).
The agonist-induced Ca2+ influx in
axolotl hepatocytes may be characterized as follows. The influx depends
totally on the generation of cAMP, which in turn acts indirectly via
protein phosphorylation catalyzed by protein kinase A (23). The influx
of Ca2+ measured in the presence
of 8-BrcAMP as a surrogate follows first-order kinetics, with a maximal
rate of ~60 nM/s and an apparent Michaelis constant of ~5 × 106 M 8-BrcAMP, as
calculated for the concentration present on the cell surface. Protein
phosphorylation(s) could be coupled to and/or modulate the open
state of an ion-gating channel in the membrane, as demonstrated for
voltage-gated ion channels (8, 9). The pharmacological profile of the
Ca2+ influx channel in amphibian
hepatocytes reveals certain relationships to these channels, as well as
to nonselective cation channels. The
Ca2+ entry shows a remarkable
dihydropyridine sensitivity but lacks the ability of voltage sensing,
indicating certain homologies to the dihydropyridine binding site of
the
1-subunit, but apparently differences in the S4 segment. Examples of other nonexcitable cells
sharing these properties have been discussed above. This relationship
is reinforced by the distinct effects of verapamil and SK&F-96365 or
Gd3+, because the selectivity of
the latter compounds for voltage-gated Ca2+ entry and nonselective cation
channels appears to be low (30, 39). The sensitivity to SK&F-96365,
Gd3+, and niflumate, all of which
act by different mechanisms (15), discloses the properties of a
receptor-activated nonselective cation channel.
This novel dihydropyridine-sensitive channel, which to our knowledge is absent in rodent liver, could serve as an example for a diversity of types and subtypes of channels in various tissues and species.
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ACKNOWLEDGEMENTS |
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The generous gift of axolotls by Prof. Dr. W. Hanke, Karlsruhe, Germany, is gratefully acknowledged.
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FOOTNOTES |
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Address for reprint requests: J. W. Kleineke, Abt. Klin. Biochemie Zentrum Innere Medizin, Univ. of Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany.
Received 4 April 1997; accepted in final form 7 July 1997.
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