1 1. Medizinische Klinik und 2 Anatomisches Institut der Eberhard-Karls Universität Tübingen, 72076 Tübingen, Germany
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ABSTRACT |
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Concomitant Na+/H+ and
Cl/HCO3
exchange activation occurs
during stimulation of acid secretion in cultured rabbit parietal cells,
possibly related to a necessity for volume regulation during the
secretory process. We investigated whether cytoplasmic volume changes
occur during secretagogue stimulation of cultured rabbit parietal
cells. Cells were loaded with the fluorescent dye calcein, and the
calcein concentration within a defined cytoplasmic volume was recorded
by confocal microscopy. Forskolin at 10
5 M, carbachol at
10
4 M, and hyperosmolarity (400 mosmol) resulted in a
rapid increase in the cytoplasmic dye concentration by 21 ± 6, 9 ± 4, and 23 ± 5%, respectively, indicative of cell
shrinkage, followed by recovery to baseline within several minutes,
indicative of regulatory volume increase (RVI). Depolarization by 5 mM
barium resulted in a decrease of the cytoplasmic dye concentration by
10 ± 2%, indicative of cell swelling, with recovery within 15 min, and completely prevented forskolin- or carbachol-induced
cytoplasmic shrinkage. Na+/H+ exchange
inhibitors slightly reduced the initial cell shrinkage and
significantly slowed the RVI, whereas 100 µM bumetanide had no
significant effect on either parameter. We conclude that acid secretagoguges induce a rapid loss of parietal cell cytoplasmic volume,
followed by RVI, which is predominantly mediated by
Na+/H+ and
Cl
/HCO3
exchange.
stomach; parietal cells; sodium/hydrogen exchanger; sodium-potassium-chloride cotransporter; regulatory volume increase; calcein; confocal microscopy; acid secretion
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INTRODUCTION |
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THE
STOMACH SECRETES ~2 liters of gastric juice per day, a fluid
mainly consisting of H+, Cl, K+,
and water. Transport pathways for H+, Cl
, and
K+ have been identified in the apical membrane of the
secreting parietal cell, but not for water. Quite the contrary,
isolated apical membrane vesicles from secreting gastric mucosa,
so-called "stimulation-associated" vesicles, were found to have a
very low water permeability (31). Therefore, it has been
assumed that the water permeates through paracellular pathways.
However, we and others observed a strong immunoreactivity of
parietal cell basolateral membranes with antibodies against aquaporin-4 (21, 27, 44), and it has
recently been shown that the aquaporin-4 knockout mouse has a reduced
pentagastrin-stimulated acid secretion (19), suggesting
that water uptake into the parietal cell is necessary for acid
secretion. Moreover, we had observed that acid secretagogues activate
parietal cell Na+/H+ exchange, but that in the
presence of CO2/HCO3, this activation is
not associated with an increase in intracellular pH
(pHi) or basolateral proton efflux, suggesting
1) that a Cl
/HCO3
exchanger
is activated concomitantly and 2) that the physiological role for Na+/H+ exchange activation during
stimulation of acid secretion is not to increase parietal cell
pHi (1). Since the concomitant activation of
Na+/H+ and
Cl
/HCO3
exchange is one of the known
mechanisms that cells use to increase their volume (20),
we speculated that the secretagogue-induced Na+/H+ exchange activation may occur in the
context of parietal cell volume regulation. Therefore, we investigated
1) whether the cytoplasmic volume of parietal cells in
primary culture changes during stimulation of acid secretion,
2) whether parietal cells regulate their cell volume during
this process, and 3) whether Na+/H+
exchangers are involved in the volume regulation observed after stimulation of acid formation.
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MATERIAL AND METHODS |
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Materials. The materials used for cell preparation and culture were the same as previously described (1, 33). Dimethylamiloride (DMA), forskolin, and carbachol were from Sigma (Deisenhofen, Germany); the acetoxymethyl ester of 2',7'-biscarboxyethyl-5(6)-carboxyfluorescein (BCECF/AM) and calcein/AM were purchased from Molecular Probes (Leiden, The Netherlands). 4-Isopropyl-3-methylsulfonylbenzoyl-guanidine methanesulfonate (Hoe-642) was a generous gift from Hoechst (Frankfurt, Germany).
Cell isolation and culture. Cell isolation and culture was carried out as previously described (1, 33). Parietal cells for volume measurements were used during the first 3 days after plating, when they have still retained a relatively round shape.
Cytoplasmic volume measurements. During stimulation of acid secretion, a network of parietal cell intracellular membrane structures enlarges to become the so-called "secretory membranes" into which the acid is secreted (13, 16). In isolated parietal cells, gastric glands, or cultured parietal cells, these secretory membranes enlarge into vacuolar structures, whose interior becomes acidic (2, 5, 28). Because of these marked vacuolar volume changes, total cell volume changes are unlikely to parallel cytoplasmic volume changes (which we wanted to measure). We therefore used fluorescence optical measurements to assess the concentration change of the intracellularly trapped dye calcein within a defined intracellular volume as a reflection of cytoplasmic volume changes. Calcein was used as the fluorescent probe because it is well retained in viable cells (9), is insensitive to pHi changes (11), and has been used by others to monitor cell volume changes (24).
Parietal cells cultured on coverslips were incubated with 3 µM calcein-AM for 30 min at 37°C in perfusion buffer (in mM: 118 NaCl, 22 NaHCO3, 14 HEPES, 7 Tris, 3 KH2PO4, 2 K2HPO4, 1.2 CaCl2, 1.2 MgSO4, and 20 glucose, pH 7.4, gassed with 5% CO2-95% O2), then washed twice and incubated a further 30 min in buffer without dye. The coverslips were then mounted in a custom-made heated perfusion chamber that allowed extremely fast buffer change. Measurements were performed using a model LSM 410 inverted laser-scanning microscope (Carl Zeiss, Oberkochen, Germany). The light from a single-line argon laser (488 nm) was directed through the objective (Plan Neofluar, 40×/1.3 NA, oil immersion). Emitted fluorescence was directed through a long-pass filter (LP 515, Zeiss), resulting in a 1,000-fold reduction of the light intensity, and a pinhole of 20 (which defines the accuracy of one point in the xy-plane, not relevant for z-scans) before it was detected by a photomultiplier. A time series of z-scans (z-step height of 1 µm) was made through the middle of a parietal cell. The thickness of optic sectioning in the z-plane was ~500 nm. The duration of each z-scan was ~1.5 s, and the interval between scans was 15 s in the first 5 min of the experiment and 30 s thereafter. The perfusion buffer was changed 90 s after the start of the z-scan series to the experimental solution. The images were analyzed utilizing the integrated software. An area within the cytoplasm was marked, fluorescence intensity was measured, and the voxels in each 1 µm3 within this area in all z-scans of the series were calculated. This procedure was used to maximize the scanning speed and to minimize the light exposure. A series of z-scans were made to assess dye bleaching/dye leakage over time and to construct a bleaching curve for subtraction (Fig. 1). The percentage of dye bleaching/dye leakage over the 20 min of the experiment was found to be ~10%. If the initial recordings before the switch to the test solution did not show a horizontal slope, then the experiment was discarded. Background fluorescence was found to be negligible and was not corrected for. If vesicles appeared within or enlarged into the selected intracytoplasmic areas, if the cells detached or moved during the rapid perfusion, or if bleaching/leakage was pronounced, then the measurement was stopped or the experiment was not used after evaluation.
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Statistics. To assess the effect of inhibitors on volume regulation, we compared the slopes of the individual time courses for calcein concentration change of the control and the inhibitor-treated cells in the linear phase of volume recovery using the Student's t-test or the Spearman rank test for paired samples. Identical time periods of the scans were compared between control and inhibitor-treated cells; n = number of separate experiments. Results were considered significant if P < 0.05.
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RESULTS |
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Changes in parietal cell morphology during stimulation of acid
formation.
Figure 2 shows a z-scan
through three parietal cells on the second day of culture, before and
15 min after stimulation with 105 M forskolin. Albeit the
chosen picture is an extreme example of variability, it is evident that
cellular morphology may vary considerably within individual cells.
Although one cell has no discernible intracellular vacuoles and does
not develop any during stimulation, one has large vacuoles that further
enlarge during stimulation, and a third has small vacuoles that enlarge
during stimulation. Experiments with a conventional fluorescent
microscope and the fluorescent dye 9-aminoacridine has shown that the
pH in these vacuoles is acidic, indicative of acid formation ongoing in
cultured parietal cells in the resting state, and becomes more acidic
when stimulated (38). All cells stain for
H+-K+-ATPase and also show other morphological
features of parietal cells (1). The variability of
individual parietal cells in culture to acid secretagogues has been
observed before (4). We usually selected parietal cells
with small- or medium-size intracytoplasmic vesicles that enlarged
during stimulation for assessment of volume changes.
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Parietal cell cytoplasmic volume changes due to changes in medium
osmolarity and depolarization.
When parietal cells are stimulated, they form secretory membranes
throughout their cytoplasm, which represents the apical membrane of the
stimulated parietal cell. This is also observed in cultured parietal
cells, in which vesicles appear or enlarge that progressively acidify.
Thus total parietal cell volume may not correlate with cytoplasmic
volume during stimulation of acid secretion. The latter, however, is
likely the regulated parameter. Therefore, we assessed cytoplasmic
volume changes by measuring the concentration change of a fluorescent
dye within a defined intracellular volume by confocal microscopy. To
validate the method, we investigated whether passive volume changes,
induced by changes of the medium osmolarity or depolarization, resulted
in the expected cytoplasmic volume changes. Switching the medium
osmolarity from 300 to 400 mosmol/l resulted in a transient
increase in cytoplasmic calcein concentration by 23 ± 5% at
200 s, indicative of cell shrinkage, followed by recovery to
baseline within 13 min, indicative of a regulatory volume increase
(RVI) (Fig. 3A). When 500 µM
DMA and 100 µM bumetanide were applied together with the hyperosmolar medium, the percentage of volume loss was reduced to 16 ± 4% and the slope of recovery was reduced by 35% (Fig. 3, B and
C). The results were not different when only 500 µM DMA
was applied (42% reduction of recovery, data not shown). It was not
our aim to study parietal cell volume recovery mechanisms after
hyperosmolar shrinkage, but, because of the less pronounced
contribution of Na+/H+ exchange, they appear
different than after secretagogue-associated shrinkage. Since the
concomitant application of a secretagogue and hyperosmolarity results
in a marked reduction of acid formation in isolated parietal cells
(data not shown), it was clear to us that passive and
secretagogue-associated shrinkage may result in totally different
intracellular ion compositions, and parietal cells shrunken by
different methods may use different means of volume recovery.
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Effect of forskolin and carbachol on parietal cell cytoplasmic
volume.
The application of 105 M forskolin, which at this
concentration elicits a rapid stimulation of acid formation in cultured
parietal cells, resulted in a rapid increase in cytoplasmic dye
concentration with a maximum of 21 ± 6% after 120 s,
indicative of cell shrinkage, followed by recovery to baseline within
the next 6 min (Fig. 4A). The
rapidity of shrinkage, which was much faster than the enlargement of
intracellular vesicles, suggested to us that volume loss occurred secondary to opening of basolateral K+ channels in addition
to apical Cl
and K+ channels. Barium, 5 mM,
resulted in cell swelling and prevented forskolin-induced cell
shrinkage (data not shown). Carbachol, 10
4 M, is a weaker
agonist of acid formation in rabbit parietal cells, resulting in
~50% of the [14C]aminopyrin uptake rates compared with
10
5 M forskolin (1). Interestingly,
carbachol also resulted in a rapid cell shrinkage, but only by 9 ± 4%, with recovery within 5 min (see Fig. 6A).
This indicates that the magnitude of cell shrinkage correlates with the
acid stimulatory capacity of the secretagogue. A comparison of Figs.
3C, 4C, and 6C demonstrates that the
speed of recovery is not directly linked to the magnitude of cell
shrinkage, because the recovery was slower after hyperosmolarity- compared with forskolin- or carbachol-associated shrinkage but may be
influenced by direct agonist-induced activation of volume regulatory
mechanisms. Again, 5 mM barium resulted in cell swelling and completely
prevented carbachol- or forskolin-induced shrinkage (data not shown).
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Effect of Na+/H+ exchange and
Na+-K+-2Cl cotransport inhibition
on secretagogue-induced cytoplasmic volume changes.
Na+/H+ exchangers have been shown to be
involved in RVI in several cell types (15,
20, 30). We have previously demonstrated that
forskolin activates Na+/H+ exchange in cultured
parietal cells and that the involved isoforms are NHE1 and NHE4
(1). Since high DMA concentrations are needed to inhibit
NHE4, we tested the effect of 500 µM DMA on forskolin-induced parietal cell volume changes. DMA reduced forskolin-induced cell shrinkage by ~25% (Fig. 4), as had been found with hyperosmolarity, inhibited the speed of volume recovery by 60%, and prolonged the time
to complete recovery from ~6 min to ~16 min. A low concentration of
DMA (10
5 M) did not result in a significant reduction in
the speed of volume recovery, suggesting that the effect of DMA is
primarily due to Na+/H+ exchange inhibition and
not due to inhibition of an amiloride-sensitive Na+
channel. In many cell types, the bumetanide-sensitive
Na+-K+-2Cl
cotransporter, which
is also expressed in the stomach (14), is involved in
RVI. We therefore investigated whether inhibition of
Na+-K+-2Cl
cotransport by 100 µM bumetanide had an effect on forskolin-induced parietal cell volume
changes. Bumetanide had no significant effect on forskolin-induced
shrinkage or recovery (Fig. 5) and, when added together with DMA, did not result in a stronger inhibition of
recovery than DMA alone (Fig. 4C). Therefore, the
Na+-K+-2Cl
cotransporter
does not appear to regulate volume in acid-secreting parietal cells.
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DISCUSSION |
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In this study, we have shown that 1) isolated rabbit
parietal cells in primary culture are able to regulate their cell
volume after hyperosmolarity-induced cell shrinkage and
depolarization-induced swelling; 2) secretagogue activation
causes cytoplasmic shrinkage, from which parietal cells recover even
more rapidly than after hyperosmolar shrinkage; and 3)
Na+/H+ exchange is one of the mechanisms of
rabbit parietal cell RVI after secretagogue activation, whereas
Na+-K+-2Cl cotransport appears
not to be involved during RVI in this cell type.
Despite considerable scientific interest in the parietal cell pathways
for ion and fluid movement, nothing is known about the ability of
gastric parietal cells for volume regulation and the involved ionic
mechanisms (20). This is probably due to the fact that
membrane and cytoskeletal perturbances occur during any form of
enzymatic parietal cell or gastric gland isolation and the freshly
isolated cells swell. A few years ago, Chew and colleagues
(5) developed a method for culture of parietal cells for a
period of several days and reported an increased sensitivity of these
cultured cells to secretagogues. It was further shown that these cells
develop a polarized distribution of membrane proteins and that they
secrete acid into intracellular secretory vesicles whose membrane
contains the apical proteins involved in HCl secretion and which
enlarge during stimulation (4, 25, 41). Although this latter feature suggests that they do
not fully resemble native parietal cells in situ, probably due to the
lack of specialized cellular contacts, they proved useful for the study
of signal transduction (4, 6,
7), cellular trafficking events (3), and gene
transcription (17, 29). We adapted this
technique for the fluorometric study of ion transport processes and
found, for example, that the Na+/H+ exchange
rate stimulated by a given low pHi was markedly higher in
the cultured cells compared with freshly isolated cells
(33, 36). Moreover, we found that, in
contrast to the situation in freshly isolated parietal cells,
secretagogues strongly stimulated Na+/H+
exchange in cultured parietal cells (1, 37).
Interestingly, a concomitant pHi increase and proton efflux
was only observed in the absence, not in the presence, of
CO2/HCO3. Since the latter is the
physiological situation, this suggested to us that 1) the
physiological significance of secretagogue-induced Na+/H+ exchanger activation does not lie in an
increase in pHi and that 2)
Cl
/HCO3
exchange activation is likely
occurring concomitantly with, and not sequentially to and caused by,
Na+/H+ exchange activation, as has been
previously suggested (28). Since the concomitant
activation of Na+/H+ and
Cl
/HCO3
exchange is one mechanism for
RVI, we speculated that parietal cells may shrink during stimulation of
acid secretion and that the observed Na+/H+
exchange activation was related to a parietal cell volume regulatory phenomenon during stimulation of acid secretion.
The present investigation demonstrates that secretagogue
stimulation of cultured parietal cells does indeed result in a rapid cytoplasmic shrinkage, followed by volume recovery. It was not the aim
of the present study to define the cellular mechanisms of this
secretagogue-induced shrinkage, but we believe that the concomitant activation of basolateral K+ channels and
apical K+ and Cl channels will be the
predominant reason for cellular volume loss. Parietal cells possess
both Ca2+- and cAMP-activated basolateral K+
channel (43), at least one, possibly more, apical
K+ channel (32), and a cAMP-activated
(9, 23, 39) and possibly a
Ca2+-activated apical Cl
channel
(10), and each of our agonists has likely activated a
different set of channels. Interestingly, the shrinkage observed with
forskolin and carbachol paralleled their acid stimulatory capacity in
cultured gastric parietal cells (1), suggesting a causal
relationship. DMA, 500 µM, caused an ~25% reduction of both
hyperosmolarity- and forskolin-induced cell shrinkage, probably due to
a direct or indirect, via a pHi decrease, effect on
K+ channels. McLeod and Hamilton (22) have
found that in isolated enterocytes, cellular volume decrease after
nutrient-induced mild swelling requires Na+/H+
exchange activation and that the Na+/H+
exchanger-induced alkalinization was essential for the activation of a
K+ channel. In cultured parietal cells, an alkalinization
does not appear essential for cell shrinkage, since none occurs in the presence of 500 µM DMA, whereas the cells shrink still to 75% of the
control value.
Secretagogue-induced Na+/H+ exchange activation
occurs concomitantly with the onset of cellular volume loss
(1). Rabbit parietal cells express NHE1, NHE2, and NHE4
(35), and we have found that the forskolin-induced
Na+/H+ exchange activation is mediated largely
by NHE4 (1). The high DMA concentrations necessary to
inhibit NHE4 reduced the speed of recovery by >60%, consistent with
an important role of Na+/H+ exchangers in
parietal cell volume regulation during acid secretion. However, this
DMA concentration would likely also inhibit an epithelial sodium
channel that has been described to mediate a part of volume recovery in
hepatocytes (45) and, furthermore, exert secondary effects
due to the strong pHi decrease during DMA treatment.
Therefore, we also studied carbachol-induced volume changes in cultured
rabbit parietal cells. We have previously shown that carbachol
predominantly activates the NHE1 isoform in cultured rabbit parietal
cells and that 1 µM Hoe-642 is able to inhibit this activation almost
completely and very specifically (1). We have further
found that in cultured parietal cells, even prolonged preincubation
with 1 µM Hoe-642 does not influence basal- and forskolin-stimulated
acid formation and that the pHi decrease observed under 1 µM Hoe-642 is rather mild and transient (40). Thus we
speculated that if the carbachol-induced NHE1 activation was related to
a volume regulatory phenomenon, we may inhibit the RVI after
carbachol-induced shrinkage by selectively inhibiting NHE1. This was
indeed the case. Therefore, the results of this study strongly support
the concept that, in rabbit parietal cells, the NHE isoforms activated
during stimulation of acid secretion play an important role in the
volume regulation necessary during acid secretion. The fact that the
activation of Na+/H+ exchange is not
accompanied by a pHi increase demonstrates that a
Cl/HCO3
exchange process, likely the
AE2 isoform, which is strongly expressed in rabbit parietal cells
(34, 42), is activated concomitantly.
However, volume recovery was not completely prevented by
Na+/H+ exchange inhibition, indicating that
other mechanisms may exist for a RVI in rabbit parietal cells.
Inhibition of the bumetanide-sensitive Na+-K+-2Cl cotransporter NKCC did
not result in an additional inhibition of volume recovery, suggesting
that in rabbit parietal cells, this transporter is not involved in
secretagogue-associated volume regulation. We also observed no effect
of bumetanide on forskolin-stimulated acid formation in cultured rabbit
parietal cells, and although bumetanide causes a marked reduction in
short-circuit current in isolated mouse gastric mucosa in the Ussing
chamber, it has no effect on forskolin-stimulated acid secretion (data
not shown). This suggests that although NKCC is clearly involved in
gastric Cl
transport, it is not a Cl
supply
mechanism in acid-secreting parietal cells, as has been speculated
(18). This is further supported by the normal low gastric
pH of NKCC knockout mice (12). Recent immunohistochemical data show that NKCC1 antibodies stain only parietal cells in the base
of the glands and that these parietal cells do not stain with AE2
antibodies, suggesting that they may not mediate HCl secretion but may
instead mediate NaCl or KCl secretion (26). Since
we have chosen parietal cells that responded to acid secretagogues with
an increase in the size in their intracellular vesicles, we may have
selected parietal cells that secrete acid, as was our aim, and thus not
studied those parietal cells that express an NKCC.
Additional putative mechanisms for the DMA-insensitive volume
increase are 1) the Na+-HCO3
cotransporter NBC1, which is expressed in these cells and is activated
by a low pHi (33) but whose role in volume
regulation is as yet speculative, 2) nonspecific cation
channels, 3) the H+-K+-ATPase, which
reabsorbs K+ ions from the secretory vesicular space, or
4) the fact that after stimulation- and
low-pHi-associated depolarization, cells gradually re-swell
because the equilibrium potential for Cl
is reversed.
In summary, this study demonstrates that cultured parietal cells are a
useful model to study parietal cell volume regulatory mechanisms.
Agonists of acid secretion cause a rapid cytoplasmic shrinkage,
followed by volume recovery, which is predominantly mediated by
Na+/H+ and
Cl/HCO3
exchange.
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ACKNOWLEDGEMENTS |
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We are grateful for the advice of Markus Ritter, Ewald Wöll, and Florian Lang and for helpful discussion concerning the volume measurements.
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FOOTNOTES |
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This work was supported by Deutsche Forschungsgemeinschaft Grants Se 460/2-5 and Se 460/9-2 and a grant from the Federal Ministry of Education, Science, Research and Technology and the Interdisciplinary Center for Clinical Research (IZKF) of the University of Tübingen (Fö. 01KS9602). Thorsten Sonnentag received a stipend of the Graduiertenkolleg "Zellbiologie in der Medizin" of the Deutsche Forschungsgemeinschaft.
This work contains experiments performed by T. Sonnentag toward fulfillment of the requirements for his doctoral thesis.
Address for reprint requests and other correspondence: U. Seidler, Abteilung Innere Medizin I, Universitätsklinikum Schnarrenberg, Eberhard-Karls Universität Tübingen, Otfried-Müller Str. 10, 72076 Tübingen, Germany (E-mail: ursula.seidler{at}uni-tuebingen.de).
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. §1734 solely to indicate this fact.
Received 1 November 1999; accepted in final form 24 February 2000.
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