1 Department of Neurology and 2 Second Department of Medicine, Technical University of Munich, D-81675 Munich, Germany
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ABSTRACT |
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Enterochromaffin-like (ECL) cells are histamine-containing
endocrine cells in the gastric mucosa that maintain a negative membrane
potential of about 50 mV, largely due to voltage-gated K+ currents [D. F. Loo, G. Sachs, and C. Prinz. Am. J. Physiol. 270 (Gastrointest Liver Physiol. 33):
G739-G745, 1996]. The current study investigated the
presence of voltage-gated Ca2+
channels in single ECL cells. ECL cells were isolated from rat fundic
mucosa by elutriation, density gradient centrifugation, and primary
culture to a purity >90%. Voltage-gated
Ca2+ currents were measured in
single ECL cells using the whole cell configuration of the patch-clamp
technique. Depolarization-activated currents were recorded in the
presence of Na+ or
K+ blocking solutions and addition
of 20 mM extracellular Ca2+. ECL
cells showed inward currents in response to voltage steps that were
activated at a test potential of around
20 mV with maximal
inward currents observed at +20 mV and 20 mM extracellular Ca2+. The inactivation rate of the
current decreased with increasingly negative holding potentials and was
totally abolished at a holding potential of
30 mV. Addition of
extracellular 20 mM Ba2+ instead
of 20 mM Ca2+ increased the
depolarization-induced current and decreased the inactivation rate. The
inward current was fully inhibited by the specific L-type
Ca2+ channel inhibitor verapamil
(0.2 mM) and was augmented by the L-type
Ca2+ channel activator BAY K 8644 (0.07 mM). We conclude that depolarization activates
high-voltage-activated Ca2+
channels in ECL cells. Activation characteristics,
Ba2+ effects, and pharmacological
results imply the presence of L-type Ca2+ channels, whereas
inactivation kinetics suggest the presence of additional N-type
channels in rat gastric ECL cells.
high-voltage-activated calcium channels; histamine; calcium; patch clamp
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INTRODUCTION |
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ENTEROCHROMAFFIN-LIKE (ECL) cells are
histamine-producing cells in the gastric mucosa that control the
peripheral regulation of acid secretion. This cell type is responsible
for histamine secretion during food-stimulated acid secretion (11, 16). Histamine in ECL cells is stored in electron-empty cytoplasmatic vesicles. Thereby, ECL cells display a close similarity to chromaffin cells of the adrenal gland or neuroendocrine pancreatic cells (5, 11,
16). Similar to chromaffin cells, ECL cells maintain a negative
membrane potential of 50 mV and intracellular
Ca2+ levels of 50 nM under resting
conditions (14, 16-19). Therefore, Ca2+ and
Ca2+ channels may be of critical
importance for ECL cell homeostasis and histamine secretion.
In previous experiments, we employed patch-clamp techniques to detect
K+ and
Cl channels in single ECL
cells (14). These studies showed that ECL cells are electrically
nonexcitable cells, as defined by the absence of voltage-gated
Na+ channels, and have a resting
potential of about
50 mV with depolarization-activated K+ channels and gastrin-induced
Cl
currents (14).
Additional voltage-activated Ca2+
currents could not be detected due to the interference with other membrane currents.
Several types of voltage-gated Ca2+ channels have been described in excitable and nonexcitable cells (1, 2). High-voltage-activated Ca2+ channels (HVACC) and low-voltage-activated Ca2+ channels are defined by their activation characteristics. High-voltage-activated channels can be further classified by their inactivation characteristics into L- or N-type channels, which show slow or fast inactivation, respectively (1, 2, 4, 6-8, 12). In analogy to chromaffin cells, which are known to express HVACC, such as L- and N-type channels, Ca2+ channels might also play a pivotal role in ECL cells. In the current study, we employed patch-clamp techniques to demonstrate the presence of voltage-activated Ca2+ channels in ECL cells. We have identified these channels by activation and inactivation kinetics, effects of Ba2+ and Ca2+ addition, and pharmacological characterization. Our results show that L-type and possibly additional N-type Ca2+ channels are present in ECL cells.
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MATERIALS AND METHODS |
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Cell isolation and primary culture. All reagents and buffer constituents were of analytical grade and were purchased from the indicated suppliers: pronase E (Boehringer Mannheim, Mannheim, Germany); N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES; Serva, Heidelberg, Germany); nycodenz (Accurate Chemical); bovine serum albumin (Serva); Cell-Tak (Becton-Dickinson, Heidelberg, Germany); fetal bovine serum (GIBCO, Eggenstein, Germany); and dithiothreitol, acridine orange, trypan blue, Dulbecco's modified Eagle's medium-F-12 medium, gentamicin, insulin, transferrin, sodium selenite, hydrocortisone, and rat gastrin-17 (Sigma, Munich, Germany).
Mucosal cells from the stomachs of female Sprague-Dawley rats (n = 5/experiment; body weight 180-200 g; Charles River, Sulzfeld, Germany) were isolated by pronase E digestion (1.3 mg/ml) using an everted sac technique (16). The resulting crude cell preparation was fractionated by counterflow elutriation using the JE 6B rotor (Beckman Instruments, Glenrothes, UK) run in a J2-21 M/E Beckman centrifuge. The original method and modifications (14, 17, 18) have been described previously. Briefly, 1 × 108 crude cells were loaded into a standard chamber at a flow rate of 16 ml/min and a rotor velocity of 2,300 revolutions/min. Small cells (diameter <10 mm) were collected at 23 ml/min and 2,000 revolutions/min. For further purification, 7 ml of this cell fraction were overlaid above two different layers of nycodenz (supplemented with 1.2 mM MgCl2, 10 mM HEPES, and 10 mg/ml bovine serum albumin, pH 7.4) diluted 1:1 or 1:2 with buffer (140 mM NaCl, 1.2 mM MgSO4, 1.0 mM CaCl2, 15 mM HEPES, 11 mM D-glucose, 10 mg/ml bovine serum albumin, and 0.5 mM dithiothreitol). After centrifugation (3 min acceleration, 6 min at 209 g, 3 min deceleration; Rotanta, Hettich, Tuttlingen, Germany), a volume of 2 ml was aspirated at the interface between the top and second layer of the step density gradient at 1.052 g/ml. The aliquot contained 75-80% ECL cells, as determined by acridine orange uptake. Cell viability (trypan blue exclusion) exceeded 95%. This enriched ECL cell fraction was then placed on sterilized coverslips precoated with Cell-Tak (diluted 1:1 with 0.5 M NaHCO3). Cells were cultured in Dulbecco's modified Eagle's medium-F-12 medium supplemented with 2 mg/ml bovine serum albumin, 5% fetal bovine serum, 10 mg/ml gentamicin, 5 mg/l insulin, 5 mg/l transferrin, 5 mg/l sodium selenite, 5 nM hydrocortisone, and 1 pM gastrin. After 48 h of culture, 90-95% of total adherent cells were identified as ECL cells by acridine orange uptake. Acridine orange is a weak base that is accumulated in acidic spaces, thereby undergoing a metachromatic shift of the dye. Because histamine in ECL cells is stored in acidic vesicles, ECL cells stained with acridine orange show a bright red fluorescence in cytoplasmatic vesicles (5, 16).
Patch-clamp methods. Cells in
short-term culture (3-4 days) were used for electrophysiological
experiments, as described previously (10). The cells were placed in a
transparent chamber and viewed with a Zeiss Axiovert inverted
microscope. In addition to their high purity, ECL cells were visually
distinguished by their small size (10 mm diameter) and form. All
experiments were performed at 20°C. Previous studies have revealed
a resting membrane potential of approximately 50 mV in ECL cells
(14). Therefore, current clamp experiments to analyze membrane
potentials were not performed in the present study.
Cells were measured in the whole cell method of the patch-clamp
technique using standard methods (3). High seal resistances (>10
G) were easily obtained. Whole cell currents were measured using an
EPC9 patch-clamp amplifier (List Electronics, Darmstadt, Germany), and
data were analyzed using commercial software (pCLAMP; Axon
Instruments). After whole cell patch clamping, ECL cells were allowed
to recover for several minutes. For analysis, the currents were
digitized with 10 kHz and low pass filtered at 2 kHz.
The Ca2+ currents were recorded by
applying a series of depolarizing test pulses (with a duration of 200 ms) as indicated in Figs. 1-4. Only cells with an input resistance
>10 G were analyzed. The amplitude of the sustained current was
measured at the end point of the 200-ms test pulse, immediately before
the appearance of the capacitative transient. Leak currents were not
subtracted because the amplitude of this current was not detectable
under conditions of 10 G
input resistance. All experimental values are expressed as mean values ± SD.
Solutions. For the analysis of
Ca2+ currents, ECL cells were
bathed in the following extracellular solution (in mM): 120 choline chloride, 2 MgCl2,
and 10 HEPES. CaCl2 or
BaCl2 was added to this solution
at concentrations as indicated in Table 1.
Choline chloride was used as a substitute of
Na+ in the extracellular solution.
For the internal solution, the following composition was used (in mM):
130 CsCl, 20 tetraethylammonium chloride, 2 MgCl2, 10 ethylene
glycol-bis(-aminoethyl
ether)-N,N,N',N'-tetraacetic acid, and 10 HEPES. The pH of the solutions was adjusted to 7.3 with
CsOH, and the osmolality was adjusted to 300 osmol/kgH2O with glucose. To
reduce rundown of voltage-gated
Ca2+ currents, 4 mM ATP was added
to the internal solution shortly before each experiment.
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RESULTS |
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Voltage-gated Ca2+ currents were
analyzed in 37 different ECL cells. The voltage-gated whole cell
Ca2+ currents had small amplitudes
(between 5 and
200 pA) at a holding potential of
60 mV and extracellular
Ca2+ concentrations of 20 mM. Most
of the cells showed inward currents in the presence of
K+ and
Na+ current blocking solutions
(see MATERIALS AND METHODS). As shown in Fig.
1A for a
single ECL cell, the inward current was activated at a test potential
of around
20 mV at a holding potential of
80 mV. The
current peaked at a test potential of +20 mV and decreased at higher
potentials. Figure 1B shows the
voltage dependence of the peak current (measured immediately) and the
sustained current (measured after 200 ms). At a test potential between
+50 and +60 mV, the current was reversed into a positive current (Fig.
1B). Using a holding potential of
80 mV, we found an average peak current of
52.2 ± 11.7 pA (n = 6) and a steady-state
current of
22.8 ± 9.3 pA at a test potential of +20 mV and
20 mM extracellular Ca2+
(n = 6).
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Figure 2 shows the inactivation of the
depolarization-activated currents at different holding potentials.
These experiments were performed at constant test potentials. The
experiment of Fig. 2A (performed with
20 mM extracellular Ca2+)
demonstrated that the rate of inactivation depended on the holding potential. The rate of inactivation increased with the negativity of
the holding potential. Inactivation reached nearly 50% at a holding
potential of 100 mV during a 200-ms test pulse to +20 mV, and no
inactivation occurred at a holding potential of
30 mV (Fig.
2B). The mean percentage of the
inactivation at a holding potential of
80 mV was 52 ± 15%
(n = 6).
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Further experiments were performed with
Ba2+ added to the extracellular
solution (Fig. 3).
Ba2+ had a higher channel
permeability, resulting in a higher peak current, and showed less
inactivation at low holding potentials. In Fig.
3A, a single ECL cell was incubated
with 20 mM Ca2+, washed, and
subsequently incubated with 20 mM
Ba2+. The ECL cell was activated
by a test pulse of +80 mV from a holding potential of 60 to +20
mV with 20 mM Ba2+ or 20 mM
Ca2+ in the same cell. The peak
current with 20 mM extracellular
Ca2+ was clearly smaller than the
current that was activated with 20 mM extracellular
Ba2+. Moreover, we observed a
stronger inactivation at low holding potentials in the presence of 20 mM Ca2+. The
Ba2+-induced current inactivated
by only 8.2 ± 15% (n = 4) during a 200-ms test pulse. In Fig. 3B, the
current-voltage relationship of the peak current of a representative
ECL cell is shown; the ECL cell was infused with 20 mM
Ba2+ or 20 mM
Ca2+, and voltage was stepped from
60 mV to different test potentials (n = 3). The peak current
was increased by substitution of
Ca2+ with
Ba2+.
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As shown in Fig. 4, we further studied
pharmacological characteristics of voltage-gated
Ca2+ currents in ECL cells. In
these experiments, Ca2+ currents
were activated by increasing the membrane potential from a holding
potential between 60 and
30 mV to a test potential of +20
mV at 20 mM extracellular Ca2+.
Two representative experiments are shown in Fig. 4,
A and
B. In Fig.
4A, the
Ca2+ current was activated by
changing the membrane potential from
60 mV to a test potential
of +20 mV. The current was fully inhibited (almost 0 pA) by adding 0.2 mM verapamil to the extracellular solution. Identical results were
obtained at a test potential between 0 and +40 mV
(n = 3, data not shown). At 0.02 mM
verapamil and conditions identical to Fig.
4A (holding potential
60 mV, test pulse to +20 mV), the inhibition was reduced to ~50% but was
still effective (data not shown, n = 3). The verapamil effect was partly reversible in the cells tested
(Fig. 4A,
n = 4).
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Figure 4B shows the effect of BAY K
8644 at a holding potential of 30 mV and a test pulse step to
+20 mV. Similar results were observed at a holding potential of
60 mV. Ca2+ currents were
increased by 33% when the well-known L-type
Ca2+ channel activator BAY K 8644 (0.07 mM) was added to the extracellular solution (Fig.
4B, n = 3).
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DISCUSSION |
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Histamine in the gastric mucosa is an effective stimulant of acid
secretion and is produced, stored, and released from fundic ECL cells,
which are localized in close proximity to the parietal cells (11). In
vitro studies using isolated, highly enriched ECL cells from rat tissue
demonstrated that these cells have a negative membrane potential (14)
and secrete histamine upon gastrin stimulation via a
Ca2+-dependent process
(16-18). We have previously described the physiological characteristics of the ECL cells using this model of single ECL cells,
enabling us to study direct effects of added substances (14,
16-18). The electrophysiological features of ECL cells may parallel findings in chromaffin cells. Both cell types have a resting
membrane potential of about 50 mV and maintain a constant intracellular Ca2+ concentration
of 50 nM (5, 8, 14, 18). Chromaffin cells are known to express
voltage-gated L-type and N-type
Ca2+ channels (15). Therefore, we
investigated the presence of these channels also in gastric ECL cells.
In the current study, we measured whole cell
Ca2+ currents in ECL cells using
patch-clamp techniques. Similar to previous experiments (14), whole
cell currents were activated by depolarization steps with a minimal
potential difference of 20 mV. In contrast to previous experiments, we
blocked K+ and
Na+ currents to investigate the
role of other ions. In the absence of
K+ and
Na+, voltage-gated whole cell
currents had small amplitudes between 5 and
200 pA at a
holding potential of
80 mV. These currents were relatively small
compared with previous studies that identified membrane currents of
+400 to +800 pA in the presence of
K+ (14). In previous studies, the
current-voltage relationship of the depolarization-activated
K+ current showed outward
rectification (14). Our present findings, however, clearly indicate the
presence of additional, voltage-gated ion channels in ECL cells,
presumably Ca2+ channels.
Depolarization of ECL cells induced an inward current under the present
experimental conditions at a test potential range of 20 to +40
mV. K+ was substituted by
Cs+, and
Na+ was replaced by choline; thus
Ca2+ were the only extracellular
cations capable of producing an inward current. Cations such as
Ca2+ enter the plasma membrane
after the electrochemical gradient. Under our experimental conditions,
Ca2+ were the only cations in the
extracellular space with a significant electrochemical, inward directed
driving force. Cs+ were the only
cations in the intracellular space that follow an outward directed
electrochemical gradient. In the presence of
K+ and
Na+ blocking solutions,
Ca2+ currents were detected as
inward (=negative) currents in a potential range of
20 to +40
mV. At potentials between +50 and +60 mV shown in Fig.
1B, the current reversed to an outward
current. The reversal of this current may reflect efflux of
Cs+.
The current-voltage relationship of the inward current in single ECL
cells corresponded to the kinetics of HVACC (Figs. 1 and 2).
Low-voltage-activated Ca2+
currents such as T-type Ca2+
channels known to be activated at a more negative membrane potential (below 50 mV) were not detected. HVACC such as L- and N-type channels typically reveal activation of the inward current at a
membrane potential of
30 to
20 mV (1, 2, 4-9). As
shown in Fig. 1, A and
B, the peak and sustained currents
were activated at a membrane potential range between
20 and +40
mV and showed an inward (=negative) current. Maximal activation was
observed at a membrane potential of +20 mV and 20 mM extracellular
Ca2+. The current-voltage
relationship therefore suggests that high-voltage-activated channels
such as L- and N-type channels are present in ECL cells.
L- and N-type Ca2+ channels show
different inactivation kinetics and are characterized by slow
inactivation (within minutes) or fast inactivation (within seconds),
respectively (1, 2). Moreover, N-type
Ca2+ channels are inactivated at
more negative membrane potentials (80 to
100 mV), whereas
L-type channels remain open (2, 7). The experiments shown in Fig. 2,
A and
B, investigated the inactivation kinetics within 200 ms. At a holding potential of
30 mV, no
inactivation of the current was observed. However, at more negative
holding potentials, we observed ~50% inactivation of the inward
currents at a holding potential of
100 mV (Fig. 2), typical for
N-type channels (2, 4, 9, 13). Because N-type channels were inactivated
by only 50%, it can be concluded that the remaining current was
mediated by L-type channels. Therefore, our findings regarding the
inactivation kinetics suggest that L-type and N-type channels are
present in ECL cells.
Addition of Ba2+ (Fig. 3) instead of Ca2+ increased the inward current. Ba2+ has a greater permeability for Ca2+ channels than Ca2+ itself (13). It has been previously reported that Ba2+ is well permeable for L-type Ca2+ channels and decreases the inactivation rate, which is consistent with our present observations (4). After replacement of Ca2+ with Ba2+ during the experiment, the tail current decreased slightly (<10%), as shown in Fig. 3A. Because this experiment was performed with a single ECL cell infused continuously over 15-25 min with different solutions, it may be that the continuing clamp conditions finally interfered with ECL cell viability. Yet, the tail current was decreased by <10%, indicating that the integrity of the cell response was still viable.
Our present results provide direct pharmacological evidence for the
presence of voltage-activated L-type
Ca2+ channels in ECL cells.
Because the activation and inactivation kinetics in our studies
suggested that L- and N-type channels might be present, we
performed additional experiments with hyperpolarized membrane
potentials (60 and
30 mV) in which N-type channels are
less activated. Verapamil is a well-tested inhibitor of
high-voltage-gated L-type Ca2+
channels (20). As shown in Fig. 4A,
the membrane potential was stepped from a holding potential of
60 mV to a test pulse of +20 mV, achieving maximal currents and
better comparisons. Verapamil blocked the
Ca2+ currents of ECL cells almost
completely.
Furthermore, the effect of the specific L-type
Ca2+ channel activator BAY K 8644 was investigated on Ca2+ currents
in ECL cells (Fig. 4B). The membrane
potential was stepped from 30 to +20 mV. At this potential, no
inactivation and thereby no activation of N-type channels can be
observed, allowing specific activation of L-type
Ca2+ channels by BAY K 8644. The
Ca2+ current was increased by BAY
K 8644, supporting the idea that ECL cells have
Ca2+ channels that display
properties of L-type Ca2+
currents.
Our current work strongly suggests the presence of voltage-gated L- and N-type Ca2+ channels in ECL cells. The physiological mechanism that leads to depolarization of HVACC in ECL cells is currently unknown. Voltage-gated Ca2+ channels were originally described in excitable cells, such as chromaffin cells of the adrenal glands (7). In chromaffin cells, acetylcholine stimulates epinephrine secretion via depolarization and activation of HVACC. Ca2+ entry through HVACC in this cell type, which is the triggering event for catecholamine secretion (15), in turn activates K+ currents (21). These currents inhibit the voltage-activated Ca2+ channels, decrease intracellular Ca2+ concentration, and finally restore the membrane potential in chromaffin cells. ECL cells, despite their great structural similarities to chromaffin cells, are electrically nonexcitable. It may be speculated that stimulation of ECL cells with gastrin would result in depolarization of ECL cells, which in turn could stimulate HVACC and/or which could stimulate Ca2+-activated outward-rectifier K+ currents, as anticipated in earlier studies (14, 21). Our current data, however, only demonstrate the presence of HVACC in ECL cells but do not allow conclusions on whether stimulation of ECL cells with gastrin finally leads to activation of HVACC.
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ACKNOWLEDGEMENTS |
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This work was supported by grants of the Deutsche Forschungsgemeinschaft (DFG PR 411/2-1 and P4 411/2-2) and by a grant from the Technical University of Munich (HSP II, 230-11/814/91).
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FOOTNOTES |
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Address for reprint requests: C. Prinz, II Medizinische Klinik, Technical Univ., Ismaningerstrasse 22, D-81675 Munich, Germany.
Received 12 July 1996; accepted in final form 14 October 1997.
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