Departments of 1 Medicine II and 2 Anatomy, Technical University of Munich, D-81675 Munich, Germany
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ABSTRACT |
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Enterochromaffin-like (ECL) cells play a pivotal role in the peripheral regulation of gastric acid secretion as they respond to the functionally important gastrointestinal hormones gastrin and somatostatin and neural mediators such as pituitary adenylate cyclase-activating peptide and galanin. Gastrin is the key stimulus of histamine release from ECL cells in vivo and in vitro. Voltage-gated K+ and Ca2+ channels have been detected on isolated ECL cells. Exocytosis of histamine following gastrin stimulation and Ca2+ entry across the plasma membrane is catalyzed by synaptobrevin and synaptosomal-associated protein of 25 kDa, both characterized as a soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein. Histamine release occurs from different cellular pools: preexisting vacuolar histamine immediately released by Ca2+ entry or newly synthesized histamine following induction of histidine decarboxylase (HDC) by gastrin stimulation. Histamine is synthesized by cytoplasmic HDC and accumulated in secretory vesicles by proton-histamine countertransport via the vesicular monoamine transporter subtype 2 (VMAT-2). The promoter region of HDC contains Ca2+-, cAMP-, and protein kinase C-responsive elements. The gene promoter for VMAT-2, however, lacks TATA boxes but contains regulatory elements for the hormones glucagon and somatostatin. Histamine secretion from ECL cells is thereby under a complex regulation of hormonal signals and can be targeted at several steps during the process of exocytosis.
histidine decarboxylase; exocytosis; neuroendocrine; high-voltage-activated calcium channels; vesicular monoamine transporter
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INTRODUCTION |
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ENTEROCHROMAFFIN-LIKE (ECL) cells are endocrine cells of the gastric mucosa, constituting ~1-3% of the fundic epithelial cell volume. ECL cells display typical features of neuroendocrine cells and can be detected by staining with bivalent cations using the Grimelius staining protocol (52, 94). Ultrastructural studies have determined that this spherical cell type 8-10 µm in diameter contains numerous secretory vesicles with electron-dense cores (1, 2, 8, 11, 13, 15, 27, 28, 31). In 1986, the presence of histamine was detected in gastric ECL cells using immunohistochemistry. In this study, ECL cells were visualized at the basis of the fundic mucosa using antibodies against histamine and the endocrine marker chromogranin A (26). Further immunohistochemical studies have confirmed that this cell type is typically located in the lower third of the gastric glands, often in close contact to chief or parietal cells (78). Localization, cellular products, and morphology of this cell type had been defined earlier by in vivo studies, yielding clear evidence for the function and importance of this cell type in the regulation of acid secretion (8, 25). In vivo studies investigating the secretory process in ECL cells, however, have been complicated by numerous neuronal, hormonal, and paracrine signals present in the gastric mucsoa. This review intends to elucidate the mechanism of histamine secretion by recent observations made in isolated ECL cells and ECL cell cultures, lacking numerous interactions and thereby allowing to test direct effects of added substances.
Histamine is a functionally important product stored in high concentrations in gastric ECL cells. It is the most important stimulus of gastric acid secretion in humans and most animals (33). Blockade of histamine receptors on gastric parietal cells is one modality of therapy of acid-related disorders like reflux esophagitis and ulcer disease of the upper gastrointestinal tract (23, 69-71, 76, 77). It was thought for some time that mucosal mast cells constituted the main source of histamine in the stomach and therefore represented the major histamine pool. Studies using isolated mast cells, however, did not detect any effect of gastrointestinal hormones on this cell type (80, 81).
Meanwhile, in vivo studies have determined that ECL cells play a pivotal role in the peripheral regulation of acid secretion. The importance of ECL cells was accentuated when hyperplasia of these cells was observed under therapy with proton pump inhibitors in humans (17, 41, 57, 79). Antisecretory therapy with proton pump inhibitors or H2-receptor antagonists resulted in an increased proliferation of ECL cells in rats and mice (2, 18, 42, 43, 56, 67, 68, 84-86, 88) and even carcinoid formation in female rats (30) after years of treatment. Although several in vivo studies determined an increased density of the ECL cells under therapy, they were unable to show a direct effect of hormones and cytokines present in the gastric mucosa. In vivo, there are complex interactions between neural, paracrine, and endocrine mechanisms. Therefore, a model of highly enriched cells was developed to test the direct effects of added substances (62).
This model of isolated ECL cells is based on the typical morphology of
this neuroendocrine cell. ECL cells are small cells that show a
characteristic electron microscopic appearance (1, 2, 8, 11, 13, 15,
27, 28, 31, 62). Histamine is accumulated in secretory vesicles. Two
arguments support the localization of histamine within these vesicles.
First, histamine release can be stimulated from permeabilized cells by
the addition of Ca2+,
indicating that histamine must be stored inside membrane-surrounded structures within the cytoplasm. Any histamine present in the cytoplasm
would be eluted using this technique.
Ca2+-induced histamine release
from permeabilized cells is a typical criterion for regulated
exocytosis, implying that histamine is stored in secretory vesicles, as
shown in previous reports investigating exocytosis from adrenal
chromaffin cells (5, 35, 36, 44). Second, secretory vesicles can be
defined as a subgroup of vesicles in ECL cells with special
ultrastructural characteristics. They contain a small electron-dense
core surrounded by a large halo. The loss of histamine following
treatment with -fluoromethylhistidine (
-FMH) plus omeprazole is
associated with a greatly reduced size of this secretory vesicle
compartment, whereas gastrin stimulation increases number and size (10,
11).
The model of isolated ECL cells uses the relatively small density (1.040 g/ml) of the cells to enrich this cell type to a purity of 85-95% (62, 65). A combination of elutriation, density gradient centrifugation, and short-term culture has been applied. The decisive advantage over in vivo studies lies in the high grade of enrichment, which allows conclusions on direct effects of test substances and intracellular steps of activation (69, 72, 76).
Figure 1 illustrates the localization of
the two key components for histamine synthesis and storage in isolated
ECL cells. In Figure 1a, isolated ECL
cells are stained with a specific antibody against the
histamine-synthesizing enzyme, histidine decarboxylase (HDC). In Figure
1b, ECL cells were incubated with a
specific antibody against the vesicular monoamine transporter subtype
2, which is responsible for the storage of histamine in secretory vesicles. Previous studies have demonstrated the presence of the vesicular monoamine transporter subtype 2 (VMAT-2) in the gastric mucosa (14, 20, 61, 92). The percentage of HDC-positive and
VMAT-2-positive cells was similar with a slightly lower percentage of
HDC-positive cells. These findings were obtained in isolated ECL cells
after 48 h of culture.
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HISTAMINE SECRETION FROM ECL CELLS |
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Histamine secretion from ECL cells is of critical importance for gastric acid secretion. In vivo studies have shown that the antral hormone gastrin is the main stimulus for acid secretion and histamine release. This hormone is released from gastrin (G) cells of the antrum after food uptake and binds to specific gastrin receptors on ECL cells (10, 25, 49, 62, 65, 70). Gastrin reaches the ECL cells via the systemic circulation. Gastrin-induced histamine release starts after 5 min and reaches its maximum after 60 min. This corresponds to in vivo data that show increased histamine secretion in the stomach 10 min after addition of gastrin (25). Isolated ECL cells respond to gastrin stimulation already after 3-5 min of incubation (62-65). Binding to the receptor leads to Ca2+ release from cytoplasmic stores and to influx of extracellular Ca2+ across the plasma membrane, which activates exocytosis of histamine vesicles. Therefore, gastrin-induced histamine secretion can be divided into three successive steps: 1) binding of gastrin to the receptor, 2) Ca2+ release from cytoplasmic stores and Ca2+ entry across the membrane, and 3) assembly of specific soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins and exocytosis of histamine.
Receptor Activation: Gastrin-Induced Histamine Release From Isolated, Highly Enriched Rat Gastric ECL Cells
Studies on isolated ECL cells showed that gastrin potently induces histamine secretion from these cells within minutes of incubation. This gastrin effect is hence classified as an acute effect on ECL cell function. In enriched, uncultured ECL cells gastrin-induced stimulation was two- to threefold. After 48 h of short-term culture, basal histamine release was 3-4% of the content, and histamine secretion was stimulated three- to sevenfold after gastrin addition, corresponding to 15-20% of the histamine content (65). Statistically significant differences of histamine in the medium were observed at 5 min after stimulation. Gastrin stimulated histamine release in a time- and dose-dependent manner after 48 h of short-term culture. The maximal effect was found to be at a concentration of 10Histamine secretion could also be stimulated by cholecystokinin
octapeptide (CCK-8). The maximal effect was achieved at a concentration
of 109 M, with an
EC50 value of 5 × 10
9 M. The equipotent
effect of gastrin and CCK-8 shows that a CCK-B receptor mediates the
gastrin effect. Gastrin/cholecystokinin receptors are divided into
CCK-A (alimentary tract) and CCK-B (brain) according to the effect of
selective receptor antagonists (89, 90). CCK-A receptors are
responsible for the impact of cholecystokinin on gall bladder
contraction, whereas CCK-B receptors mediate fear in the brain (90).
CCK-B receptors were identified in the gastric mucosa on isolated ECL
and parietal cells (3, 62, 90). The gastrin effect could be inhibited
in a dose-dependent manner by the CCK-B antagonist L-365260
(IC50 = 2 × 10
8 M), confirming that ECL
cells express membrane-bound CCK-B receptors mediating gastrin-induced
stimulation (65). Maximal inhibition was observed at an L-365260
concentration of 10
6 M. The
CCK-A antagonist L-364718 had no effect on gastrin-induced histamine
secretion at concentrations of
10
8 and
10
7 M (62).
Signal Transduction: Single Cell Analysis of Intracellular Ca2+ Levels in Isolated ECL Cells
Cells in 48-96 h primary cultures can be utilized to observe Ca2+ signals of single ECL cells with superfusion. At a chamber exchange rate of about five times per minute, cross talk from the small number of contaminating cells is prevented. Hence this approach allows direct assessment of effects of test substances added to the perfusion medium. The basal Ca2+ level in ECL cells was ~60 nM, and the intracellular Ca2+ concentration ([Ca2+]i) showed a characteristic biphasic response on gastrin stimulation: an initial peak of ~800 nM followed by an intracellular plateau of ~250 nM. By addition of CCK-B antagonists (such as L-365260), or the hormones somatostatin or galanin during the Ca2+-entry phase, the [Ca2+]i could be lowered to basal values in a dose-dependent manner, which corresponds to the dose-dependent inhibition of histamine secretion by these ligands (65, 97). Addition of the gastrin receptor antagonist L-365260 (10Addition of EGTA (10 mM) during the plateau phase of gastrin-induced signal transduction decreased [Ca2+]i to basal values corresponding to the results for histamine secretion (62). These observations suggest that the plateau phase is of functional importance for stimulation of secretion and is mediated through Ca2+ entry along the plasma membrane. Ca2+ influx during the plateau phase is probably triggered by Ca2+ released from intracellular stores during the initial peak phase. This event has been described as "Ca2+ release activated Ca2+ current" or "Ca2+-induced Ca2+ release" (60).
Exocytosis in ECL Cells: Involvement of SNARE Proteins
The presence of specific exocytotic proteins in highly enriched ECL cells was initially determined by Western blotting. The t- and v-SNARE proteins synaptosomal-associated protein of 25 kDa (SNAP-25), syntaxin, vesicle-associated membrane protein (VAMP or synaptobrevin), synaptotagmin, and synaptophysin were found in ECL cells based on immunoreactivity for SNAP-25 at 25 kDa, synaptobrevin at 18 kDa, syntaxin at 35 kDa, synaptotagmin at 65 kDa, and synaptophysin at 38 kDa (36, 98). Evidence for the presence of the SNARE proteins SNAP-25 and synaptobrevin in ECL cells of rat gastric mucosa was also obtained by immunohistochemistry and immunocytochemistry. The colocalization of these two proteins could be shown by double staining with an antibody against HDC in consecutive thin sections of the gastric mucosa as well as in isolated ECL cells (36).For analysis of the functional importance of exocytotic proteins in ECL cells, a newly developed model of permeabilized cells was applied (36). As discussed above, Ca2+ entry along the plasma membrane plays a pivotal role in histamine secretion. After permeabilization, histamine secretion should be directly induced by addition of Ca2+ bypassing the receptor-associated steps of activation. Cultured ECL cells were incubated with digitonin (8 µM) and made permeable for extracellular substances like Ca2+ and high-molecular-weight substances such as the clostridial neurotoxins.
This technique allows an analysis of intracellular mechanisms of
exocytosis in ECL cells after Ca2+
influx. Permeabilization with digitonin was found to be the optimal procedure to render the cells permeable to both
Ca2+ and the neurotoxins tetanus
toxin light chain (TeTxL) and botulinum neurotoxin A (BoNTA). These
neurotoxins inhibit exocytosis in neuronal and chromaffin cells by
specific cleavage of the exocytotic proteins synaptobrevin [TeTxL
(5, 35, 74)] and SNAP-25 [BoNTA (4, 6, 29, 37, 82)].
In this study, highly enriched ECL cells were permeabilized with
digitonin (8 µM) after 48 h of short-term culture and then
preincubated with the neurotoxins TeTxL (1 µM) or BoNTA (100 nM) for
15 min. Histamine release was stimulated by addition of
Ca2+ (30 µM) after 10 min of
incubation. ECL cells, which had not been incubated with
Ca2+, showed a basal release of
6-15% of cellular histamine content. Incubation with
Ca2+ increased the release three-
to fourfold. Preincubation of permeabilized ECL cells with 1 µM TeTxL
resulted in a distinct inhibition of Ca2+-induced secretion. These data
show that the exocytotic apparatus of ECL cells can be influenced by
TeTxL. The impact of BoNTA was tested with an identical procedure.
After preincubation of 100 nM BoNTA for 15 min, histamine secretion was
tested by addition of 30 µM free
Ca2+. BoNTA completely inhibited
Ca2+-induced histamine release
(Fig. 2). The cleavage of the exocytotic proteins SNAP-25 and synaptobrevin was also examined (36). TeTxL cleaved the exocytotic protein synaptobrevin (47, 74), whereas BoNTA
split SNAP-25 (4, 37). Other exocytotic proteins assayed were not
affected by these toxins in ECL cells (36).
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The increase of intracellular Ca2+ levels in ECL cells and other neuroendocrine cells leads to the association of different exocytotic proteins during interaction of secretory vesicles with the plasma membrane (36, 82). While synaptobrevin was identified on sections of the gastric mucosa, SNAP-25 was only detectable in protein fractions derived from purified parietal cells (59). The present immunoblots as well as the colocalization in sections and isolated cells, however, give clear evidence for the presence of these proteins in ECL cells. TeTxL completely cleaved synaptobrevin in ECL cells but partially inhibited Ca2+-induced histamine secretion. In chromaffin cells on the other hand, TeTxL totally blocks secretion but cleaves synaptobrevin only partially (35). Ca2+-induced histamine secretion from ECL cells is totally inhibited by BoNTA, although SNAP-25 is only partially cleaved. Similar results have been found in adrenal chromaffin cells (37, 44). Thus ECL cells are similar to other neuroendocrine cells by the presence of the functionally important SNARE proteins SNAP-25 and synaptobrevin, as well as the vesicle associated proteins synaptophysin and synaptotagmin, which can be found both in adrenal chromaffin and neuronal cells.
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ELECTROPHYSIOLOGICAL CHARACTERIZATION OF ECL CELLS |
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Using patch-clamp techniques, it is possible to analyze ionic
contributions to resting and stimulated cells. Whole cell currents were
measured by patch-clamp techniques (7, 50). ECL cells have a negative
resting membrane potential of about 60 mV (50). Depolarization
does not result in an action potential showing that ECL cells are
electrically nonexcitable. In the presence of
K+,
Na+, and
Ca2+, depolarization of the plasma
membrane leads to an inward current of 400 pA that has a reversal
potential of ~0 V and can be blocked by
Cs+. Under these circumstances,
depolarization of the ECL cell membrane causes an outward rectifier
K+ current (73), suggesting the
existence of a K+ channel in ECL
cells that is important for the maintenance of the resting membrane
potential. Stimulation of the cells with 12-O-tetradecanoylphorbol 13-acetate
(TPA; 10
6 M), gastrin
(10
9 M), or CCK-8
(10
7 M) does not provoke an
increased current of K+ but leads
to an additional outward current of negative ions. These ions are
probably Cl
, according to
the reversal potential. This membrane current generated by stimuli
probably originates from membrane fusion of histamine vesicles.
Histamine is accumulated in secretory vesicles of ECL cells as a
consequence of a proton gradient generated by a V-type ATPase (21).
Additional transport of Cl
into the vesicles must be present to maintain electroneutrality. During
exocytosis of the vesicles,
Cl
channels are
incorporated into the plasma membrane, and stimulation therefore
results in a Cl
current
(50).
Observations of Ca2+ currents were
also carried out by patch-clamp techniques. During these experiments,
K+ and
Na+ were substituted by
Cs+ and choline chloride in the
solution to block the currents carried by these ions and to determine
the presence of other ion currents. These experiments (7) show that
depolarization of ECL cells leads to a negative membrane current when
K+ and
Na+ channels are blocked. This
indicates that, besides K+
channels, ECL cells also express voltage-gated
Ca2+ channels. Under these
conditions, depolarization from 30 to +20 mV results in a
membrane current of about
40 pA (e.g., by an inward current of
positive ions), which can be inhibited by Ca2+ channel blockers and is
dependent on the extracellular
Ca2+ content (7). Video imaging
experiments had already shown that Ca2+ entry via the plasma membrane
is of critical importance for the activation of histamine release.
Whole cell patch-clamp experiments revealed that an influx of
Ca2+ takes place via
high-voltage-activated Ca2+
channels under blockage of K+
channels by tetraethylammonium or
Cs+ (7). The presence of L-type
Ca2+ channels is suggested by the
mechanisms of activation. The current-voltage relationship in the
hyperpolarized range (in which L-type channels remain open) suggests
that additional N-type channels are present since ~50% inactivation
was observed at a holding potential of
100 mV. The functional
importance of the N-type channels in ECL cells, however, remains to be
determined. Preliminary studies of our own group investigating the
effect of N- and L-type channel blockers on ECL cell function have
revealed that both inhibit histamine secretion and L-type blockers are
more effective (66).
Receptor binding is followed by Ca2+ influx along the plasma membrane within 20-30 s, probably through voltage-activated L-type Ca2+ channels (65). This latter Ca2+ influx is capacitative, regulated by Ca2+ release from intracellular stores, as known from other nonexcitable cell systems (60). Voltage-gated L- and N-type channels were discovered in ECL cells as well as in chromaffin cells (7, 22, 55, 60, 87). Besides the stimulus-secretion coupling, they could be responsible for the activation of K+ outward rectifier currents to maintain the membrane potential (50). Similar observations were reported from other research groups (73).
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INFLUENCE OF SOMATOSTATIN ON HISTAMINE RELEASE FROM ECL CELLS |
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Somatostatin inhibits gastrin-induced histamine secretion from isolated
and cultured ECL cells in a dose-dependent manner. Experiments on
isolated ECL cells show that somatostatin totally inhibits
gastrin-induced histamine secretion at a concentration of
107 M. The selective
somatostatin receptor agonist DC-3287 inhibits gastrin-induced histamine release at concentrations 1,000-fold below
that of somatostatin, indicating the functional importance of the
somatostatin receptor subtype 2 (SSTR-2) in ECL cells (64). Video
imaging studies on fura 2-AM-loaded ECL cells showed that addition of
somatostatin (10
7 M) or the
somatostatin receptor agonist DC-3287
(10
10 M) during the plateau
phase resulted in a decrease of
[Ca2+]i
back to basal levels corresponding to the observed inhibition of
histamine secretion. Activation of SSTR-2 receptors leads to a potent
inhibition of gastrin-induced histamine secretion from isolated and
cultivated ECL cells by preventing the entry of
Ca2+ along the plasma membrane.
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OTHER STIMULI OF HISTAMINE SECRETION FROM ECL CELLS |
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Besides gastrin, other stimuli of ECL cells were tested to provide
evidence for further receptors on these cells. Therefore, both
receptor-dependent and receptor-independent steps of activation were
determined. Histamine release was determined in acutely isolated cells.
Carbachol (104 M)
significantly stimulated histamine secretion from acutely isolated
cells (65% enrichment) (62). Carbachol had no consistent effect on
highly enriched and cultured cells, which was also observed by other
investigators (46). Therefore, ECL cells may lack muscarinic receptors.
Epinephrine (10
5 M) caused
significant stimulation. Especially effective were direct activators of
intracellular steps of activation like TPA (10
6 M), dibutyryl
adenosine 3',5'-cyclic monophosphate
(10
3 M), and forskolin
(10
5 M) (46, 62). Besides
gastrin, pituitary adenylate cyclase-activating peptide
(10
9 M) has been determined as a decisive stimulus
for histamine secretion (46, 96), which is probably of
critical importance for neural stimulation of histamine in the cephalic
phase of acid secretion.
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REGULATION OF HISTAMINE SECRETION: DIFFERENT HISTAMINE POOLS IN THE EXOCYTOTIC APPARATUS |
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Histamine secretion from intact, highly enriched ECL cells was also
determined after 60 min of preincubation with the HDC inhibitor,
-FMH (10
6 M), the
translation blocker cycloheximide
(10
6 M), the transcription
blocker actinomycin D (10
6
M), or the VMAT inhibitor reserpine
(IC50 = 5 × 10
7 M) (66). Sixty minutes
of pretreatment with each of these substances and subsequent
stimulation of histamine secretion with 1 nM gastrin attenuated the
response by 40-60%, indicating that gastrin-induced release
within 60 min of stimulation depends largely on secretion of de novo
synthesized histamine. Similar obvervations regarding the effect of
-FMH were also made using isolated perfused rat stomachs (9).
Furthermore, 4 h of preincubation with
10
6 M reserpine resulted in
complete inhibition of gastrin-induced histamine release (66).
Therefore, exocytosis of histamine is separated into different pools of
histamine either immediately released by
Ca2+ entry or secreted following
gastrin-induced de novo synthesis due to HDC stimulation.
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SYNTHESIS OF HISTAMINE BY HDC IN ECL CELLS |
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Stimulation of histamine synthesis has been classified as an
intermediate gastrin effect. HDC is the only enzyme performing histamine synthesis in ECL cells (62), which has been detected immunohistochemically on sections of the gastric mucosa and
immunocytochemically on isolated cells by specific antibody staining
(65). Thirty to sixty minutes after addition of gastrin
(109 M), an increased
activity of HDC occurs. After 60 min of incubation, HDC activity was
increased twofold in acutely isolated ECL cells and three- to fourfold
in cultured cells. The EC50 value
of gastrin for stimulation of HDC activity corresponded to that found
for induction of histamine secretion. These results are in accordance with the data obtained in vivo where HDC activity was increased after
60-120 min of incubation with gastrin (16). Similar kinetics regarding the stimulation of histamine synthesis were also observed in
basophilic leukemia cells (53).
Besides direct enzyme activation, translation of present HDC mRNA and
posttranslational regulation of HDC also seem to be of great importance
for gastrin-induced activation. Preincubation with the protein
synthesis inhibitor cycloheximide
(106 M) inhibited
gastrin-stimulated HDC activity and thereby histamine synthesis (12,
38), indicating that activation of HDC in the cytoplasm is of critical
importance for gastrin-induced secretion. Furthermore, recent
observations suggest that mammalian HDC may be synthesized as an
inactive proenzyme that requires posttranslational processing to become
active (95). Molecular cloning of the mammalian HDC has revealed that
the cDNA encodes a protein with a molecular mass of 74 kDa (40, 95),
whereas purified fetal liver protein subunits [relative mol wt
(Mr) = 54,000] or Sf9 mastocytoma cells (Mr = 53,000)
contain a protein of different size and molecular weight (83).
Furthermore, the 74-kDa isoform appears to be enzymatically inactive
(95). These discrepancies might be explained by the fact that HDC is
posttranslationally processed.
Gastrin stimulates gene expression of HDC mRNA after 2 h of incubation
(16). These reports are in accordance with the observation that
preincubation with the HDC inhibitor -FMH
(10
6 M) inhibited
gastrin-stimulated histamine secretion (1, 2). In previously published
studies, transcription of HDC was stimulated after 120 min of
incubation in transfected cells and was found to involve both
Ca2+- and cAMP-dependent
transcription factors (34). Gastrin therefore plays an important role
for histamine synthesis by HDC activation and gene expression within
hours of incubation. Gene regulation of the HDC promoter has been
investigated by molecular techniques (34). The HDC gene promoter
contains two Ca2+-responsive TATA
boxes and is under complex regulation. The upstream promoter sequence
was cut out and inserted into a cell line stably transfected with the
gastrin receptor (34). Promoter analysis showed that this promoter
sequence was stimulated by gastrin addition and was controlled by
Ca2+- and cAMP-responsive
elements. Furthermore, protein kinase C (PKC) activation resulted in
stimulation of HDC gene expression, whereas downregulation of PKC
activity decreased the enzyme activity (34).
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HISTAMINE TRANSPORT VIA THE VMAT |
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ECL cells show close similarity to certain neuronal cells of the brain stem as well as chromaffin cells of the adrenal medulla because of their ability to accumulate biogenic amines in secretory vesicles using specific transporters. Two subtypes of VMAT have been characterized. Chromaffin, enterochromaffin, and neuronal cells store epinephrine, norepinephrine, serotonin, or dopamine via activation of VMAT-1. Studies on human basophilic leukocytes and ECL cells revealed that these cells express VMAT-2 (20, 92). In contrast to the ligands discussed above, histamine is a diamine. Mast cells, in contrast, do not contain VMAT-2.
In rat ECL cells, gene sequence of VMAT-2 was detected by RT-PCR (24). Cloning and sequencing of the PCR product in ECL cells revealed a 1,345-bp open reading frame, corresponding to 515 amino acids. The VMAT-2 sequence obtained from ECL cells was 98% homologous to previously published sequences obtained in rat basophilic leukemia (RBL-2) cells (19). The presence of VMAT-2 in isolated ECL cells was also shown by immunocytochemistry, as seen in Fig. 1 and consistent with sections performed in the gastric mucosa (61).
The VMAT-2 promoter region has recently been cloned by different
research groups using the Genome Walker kit combined with nested PCR,
and identical results were achieved (24, 91). Interestingly,
translation of the VMAT-2 protein starts at exon 2, as shown in Fig.
3. Exon 1 and intron 1 are incorporated
into the promoter sequence and seem to have regulatory functions. As shown in Fig. 3, analysis of the promoter revealed no TATA boxes within
the upstream sequence. However, binding sites for AP-2, Sp1,
NFB, Ca2+, and a
cAMP-responsive element motif, as well as somatostatin- and
glucagon-responsive elements were detected (24, 91). The physiological
stimulants of histamine storage remain to be determined.
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There is close similarity between the mechanisms of vesicular uptake in ECL cells and basophilic leukocytes. The transporters in these cell types show ~100% homology (19, 48). In analogy to basophilic and chromaffin cells, there is a countertransport of the amine with protons in ECL cells. Vesicle acidification can be visualized in vitro by staining of the cells with acridine orange, which accumulates in acidic compartments (21). The stimulus of histamine uptake is currently unknown. Apparently, there is no direct involvement of gastrin in the gene regulation of the transporter, and a feedback mechanism seems possible (24). The mechanism of histamine uptake into vesicles can be inhibited by reserpine (66) and could build a basis for alternative methods for blocking gastric acid secretion (48).
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CHRONIC GASTRIN EFFECTS |
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The chronic gastrin effect on isolated ECL cells consists of
stimulation of cell proliferation within 2-4 days of incubation corresponding to in vivo studies (43, 47, 84-86). Gastrin
stimulated ECL cell mitosis, after an incubation of 24-96 h, with
an EC50 value of 4 × 1011 M (65).
Bromodeoxyuridine, a thymidine analog, which is incorporated in
single-stranded DNA during the S phase of mitosis (39), was used as a
marker for increased DNA synthesis (65). Gastrin probably stimulates
the transition from G0 to
G1 phase in ECL cells (39, 58).
While ECL cells from the rat are obviously able to divide according to
these data, this feature could not be shown in human cells. However, no
appropriate technique has yet been established for enrichment of human cells.
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CONCLUSIONS |
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Figure 4 summarizes the mechanism of
histamine secretion from rat ECL cells. Regulation of histamine
secretion from ECL cells occurs at different cellular levels (Fig.
4A). At the plasma membrane, receptor expression and receptor affinity for the hormone gastrin can
be targeted by specific receptor antagonists. Receptor affinities for
stimulation of secretion and proliferation show a remarkable difference. After receptor activation, plasmalemmal
Ca2+ channels appear to be of
great importance for stimulation of histamine release.
High-voltage-activated Ca2+
channels have been detected in ECL cells that may be involved in
stimulus-secretion coupling and also function as activators of outward
rectifier K+ currents to maintain
the membrane potential of 50 mV.
Ca2+ entry across the membrane
induces a specific assembly of the SNARE proteins SNAP-25 and
synaptobrevin (Fig. 4B). These
proteins are cleaved by clostridial neurotoxins such as TeTxL and
BoNTA, inhibiting exocytosis. After extrusion of
histamine, the biogenic amine is restored by the action of HDC. This
enzyme is stimulated by gastrin-dependent signal transduction steps but
can be inhibited by histidine analogs. Finally, histamine is
transported into the secretory vesicles, presenting another cellular
level at which histamine secretion can be blocked using substances such
as reserpine (Fig. 4C). Different
histamine pools can be detected following gastrin stimulation, since
histamine is quickly synthesized de novo and accumulated in secretory
vesicles (Fig. 4D). All of these different cellular levels may present a tool in the future to inhibit
histamine secretion from ECL cells, enabling us to treat acid-related
disorders of the upper gastrointestinal tract with novel therapeutic
agents.
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ACKNOWLEDGEMENTS |
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We are grateful to Barbara Zschiesche and Andreas Mauermayer for expert technical assistance. We thank Reinhard Jahn (Max-Plank-Institut, Göttingen, Germany) and Tsutomu Chiba (Kyoto Univ., Kyoto, Japan) for antibodies and Ulrich Weller (Univ. Mainz, Mainz, Germany), Bibhuti R. DasGupta (Univ. of Wisconsin, Madison, WI), and Clifford C. Shone (Centre for Applied Microbiology and Research, Porton Down, Salisbury, UK) for providing neurotoxins for this study.
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FOOTNOTES |
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This work was supported by Deutsche Forschungsgemeinschaft Grant Pr 411/2-2 (to C. Prinz) and Graduiertenkolleg 333: Biology of Human Diseases, by Fonds der Chemischen Industrie, and by Volkswagen-Stiftung.
This study contains work performed by Angela Galler and Robert Zanner in fulfillment of their MD theses at the Technical University of Munich.
Address for reprint requests and other correspondence: C. K. Prinz, II. Medizinische Klinik, Technische Universität München, Ismaninger Str. 22, D-81675 Munich, Germany (E-mail: christian.prinz{at}lrz.tum.de).
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REFERENCES |
---|
1.
Andersson, K.,
D. Chen,
R. Hakanson,
H. Mattsson,
and
F. Sundler.
Enterochromaffin-like cells in the rat stomach: effect of -fluoromethylhistidine-evoked histamine depletion. A chemical, histochemical and electron-microscopic study.
Cell Tissue Res.
270:
7-13,
1992[Medline].
2.
Andersson, K.,
R. Hakanson,
H. Mattsson,
B. Ryberg,
and
F. Sundler.
Hyperplasia of histamine-depleted enterochromaffinlike cells in rat stomach using omeprazole and -fluoromethylhistidine.
Gastroenterology
103:
897-904,
1992[Medline].
3.
Beinborn, M.,
Y. M. Lee,
E. W. McBride,
S. M. Quinn,
and
A. S. Kopin.
A single amino acid of the cholecystokinin-B/gastrin receptor determines specificity for non-peptide antagonists.
Nature
362:
348-350,
1993[Medline].
4.
Binz, T.,
J. Blasi,
S. Yamasaki,
A. Baumeister,
E. Link,
T. C. Südhof,
R. Jahn,
and
H. Niemann.
Proteolysis of SNAP-25 by types E and A botulinal neurotoxins.
J. Biol. Chem.
269:
1617-1620,
1994
5.
Bittner, M. A.,
and
R. W. Holz.
Effects of tetanus toxin on catecholamine release from intact and digitonin-permeabilized chromaffin cells.
J. Neurochem.
51:
451-456,
1988[Medline].
6.
Blasi, J.,
E. R. Chapman,
E. Link,
T. Binz,
S. Yamasaki,
P. De Camilli,
T. C. Südhof,
H. Niemann,
and
R. Jahn.
Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25.
Nature
365:
160-163,
1993[Medline].
7.
Bufler, J.,
G. C. Choi,
C. Franke,
W. Schepp,
and
C. Prinz.
Voltage-gated Ca2+ currents in rat gastric enterochromaffin-like cells.
Am. J. Physiol.
274 (Cell Physiol. 43):
C424-C429,
1998
8.
Capella, C.,
G. Vasallo,
and
E. Solcia.
Light and electron microscopic identification of the histamine-storing agyrophil (ECL) cell in murine stomach and its equivalent in other mammals.
Z. Zellforsch.
118:
68-84,
1971[Medline].
9.
Chen, D.,
R. Marvik,
K. Ronning,
K. Andersson,
H. L. Waldum,
and
R. Hakanson.
Gastrin-evoked secretion of pancreastatin and histamine from ECL cells and of acid from parietal cells in isolated, vascularly perfused rat stomach. Effects of isobutyl methylxanthin and alpha-fluoromethylhistidine.
Regul. Pept.
65:
133-138,
1996[Medline].
10.
Chen, D.,
H. J. Monstein,
A. G. Nylander,
C. M. Zhao,
F. Sundler,
and
R. Hakanson.
Acute responses of rat stomach enterochromaffinlike cells to gastrin: secretory activation and adaptation.
Gastroenterology
107:
18-27,
1994[Medline].
11.
Chen, D.,
C. M. Zhao,
K. Andersson,
F. Sundler,
and
R. Hakanson.
Ultrastructure of enterochromaffin-like cells in rat stomach: effects of -fluoromethylhistidine-evoked histamine depletion and hypergastrinemia.
Cell Tissue Res.
283:
469-478,
1996[Medline].
12.
Chen, D.,
C. M. Zhao,
H. Yamada,
P. Norlen,
and
R. Hakanson.
Novel aspects of gastrin-induced activation of histidine decarboxylase in rat stomach ECL cells.
Regul. Pept.
77:
169-175,
1998[Medline].
13.
D'Adda, T.,
F. P. Pilato,
M. Lazzaroni,
F. Robutti,
P. G. Bianchi,
and
C. Bordi.
Ultrastructural morphometry of gastric endocrine cells before and after omeprazole. A study in the oxyntic mucosa of duodenal ulcer patients.
Gastroenterology
100:
1563-1570,
1991[Medline].
14.
De-Giorgio, R.,
D. Su,
D. Peter,
R. H. Edwards,
N. C. Brecha,
and
C. Sternini.
Vesicular monoamine transporter 2 expression in enteric neurons and enterochromaffin-like cells of the rat.
Neurosci. Lett.
217:
77-80,
1996[Medline].
15.
Delwaide, J.,
M. Vivario,
J. Belaiche,
E. Louis,
R. Courtoy,
P. Gast,
and
J. Boniver.
Ultrastructural demonstration of histamine in human enterochromaffin like cell granules.
Gut
32:
834-843,
1991[Medline].
16.
Dimaline, R.,
and
A. K. Sandvik.
Histidine decarboxylase gene expression in rat fundus is regulated by gastrin.
FEBS Lett.
281:
20-22,
1991[Medline].
17.
Eissele, R.,
G. Brunner,
B. Simon,
E. Solcia,
and
R. Arnold.
Gastric mucosa during treatment with lansoprazole: Helicobacter pylori is a risk factor for argyrophil cell hyperplasia.
Gastroenterology
112:
707-717,
1997[Medline].
18.
Ekman, L.,
E. Hansson,
N. Havu,
E. Carlsson,
and
C. Lundberg.
Toxicological studies on omeprazole.
Scand. J. Gastroenterol. Suppl.
108:
53-69,
1985[Medline].
19.
Erickson, J. D.,
L. E. Eiden,
and
B. J. Hoffman.
Expression cloning of a reserpine-sensitive vesicular monoamine transporter.
Proc. Natl. Acad. Sci. USA
89:
10993-10997,
1992[Abstract].
20.
Erickson, J. D.,
M. K. Schafer,
T. I. Bonner,
L. E. Eiden,
and
E. Weihe.
Distinct pharmacological properties and distribution in neurons and endocrine cells of two isoforms of the human vesicular monoamine transporter.
Proc. Natl. Acad. Sci. USA
93:
5166-5171,
1996
21.
Forgac, M.
Structure and function of vacuolar class of ATP-driven proton pumps.
Physiol. Rev.
69:
765-796,
1989
22.
Gandia, L.,
R. Borges,
A. Albillos,
and
A. G. Garcia.
Multiple calcium channel subtypes in isolated rat chromaffin cells.
Pflügers Arch.
430:
55-63,
1995[Medline].
23.
Gantz, I.,
G. Munzert,
T. Tashiro,
M. Schaffer,
L. Wang,
J. DelValle,
and
T. Yamada.
Molecular cloning of the human histamine H2 receptor.
Biochem. Biophys. Res. Commun.
178:
1386-1392,
1991[Medline].
24.
Gerhard, M.,
N. Neumayer,
E. Lengyel,
E. Presecan-Siedel,
M. Classen,
and
C. Prinz.
Promoter analysis of the vesicular monoamine transporter subtype 2 in PC12 and ECL-cells (Abstract).
Gastroenterology
116:
A606,
1999.
25.
Hakanson, R.,
G. Boettcher,
F. Ekblad,
P. Panula,
M. Simonsson,
M. Dohlsten,
T. Hallberg,
and
F. Sundler.
The ECL cells.
In: Physiology of the Gastrointestinal Tract, edited by D. H. Alpers,
J. Christensen,
E. D. Jacobsen,
and J. H. Walsh. New York: Raven, 1994, p. 1171-1184.
26.
Hakanson, R.,
G. Bottcher,
E. Ekblad,
P. Panula,
M. Simonsson,
M. Dohlsten,
T. Hallberg,
and
F. Sundler.
Histamine in endocrine cells in the stomach. A survey of several species using a panel of histamine antibodies.
Histochemistry
86:
5-17,
1986[Medline].
27.
Hakanson, R.,
L. I. Larsson,
G. Liewdberg,
J. F. Rehfeld,
and
F. Sundler.
Electron microscopic identification of the histamine-containing argyrophil (enterochromaffin-like) cells in the rat stomach.
Z. Zellforsch.
122:
460-466,
1971[Medline].
28.
Hakanson, R.,
Y. Tielemans,
D. Chen,
K. Andersson,
H. Mattsson,
and
F. Sundler.
Time-dependent changes in enterochromaffin-like cell kinetics in stomach of hypergastrinemic rats.
Gastroenterology
105:
15-21,
1993[Medline].
29.
Hanson, P. I.,
J. E. Heuser,
and
R. Jahn.
Neurotransmitter releasefour years of SNARE complexes.
Curr. Opin. Neurobiol.
7:
310-315,
1997[Medline].
30.
Havu, N.
Enterochromaffin-like cell carcinoids of gastric mucosa in rats after life-long inhibition of gastric secretion.
Digestion
5, Suppl. 1:
42-55,
1986.
31.
Helander, H. F.
The cells of the gastric mucosa.
Int. Rev. Cytol.
70:
217-289,
1981[Medline].
32.
Henry, J. P.,
C. Sagne,
C. Bedet,
and
B. Gasnier.
The vesicular monoamine transporter: from chromaffin granule to brain.
Neurochem. Int.
32:
227-246,
1998[Medline].
33.
Hersey, S. J.,
and
G. Sachs.
Gastric acid secretion.
Physiol. Rev.
75:
155-189,
1995
34.
Höcker, M.,
Z. Zhang,
D. A. Fenstermacher,
S. Tagerud,
M. Chulak,
D. Joseph,
and
T. C. Wang.
Rat histidine decarboxylase promoter is regulated by gastrin through a protein kinase C pathway.
Am. J. Physiol.
270 (Gastrointest. Liver Physiol. 33):
G619-G633,
1996
35.
Höhne-Zell, B.,
A. Ecker,
U. Weller,
and
M. Gratzl.
Synaptobrevin cleavage by the tetanus toxin light chain is linked to the inhibition of exocytosis in chromaffin cells.
FEBS Lett.
355:
131-134,
1994[Medline].
36.
Höhne-Zell, B.,
A. Galler,
W. Schepp,
M. Gratzl,
and
C. Prinz.
Functional importance of synaptobrevin and SNAP-25 during exocytosis of histamine by rat gastric enterochromaffin-like cells.
Endocrinology
138:
5518-5526,
1997
37.
Höhne-Zell, B.,
and
M. Gratzl.
Adrenal chromaffin cells contain functionally different SNAP-25 monomers and SNAP-25/syntaxin heterodimers.
FEBS Lett.
394:
109-116,
1996[Medline].
38.
Hollande, F.,
S. Combettes,
J. P. Bali,
and
R. Magous.
Gastrin stimulation of histamine synthesis in enterochromaffin-like cells from rabbit fundic mucosa.
Am. J. Physiol.
270 (Gastrointest. Liver Physiol. 33):
G463-G469,
1996
39.
Jacobs, T.
Control of the cell cycle.
Dev. Biol.
153:
1-15,
1992[Medline].
40.
Joseph, D.,
P. Sullivan,
Y. Wang,
C. Kozak,
D. A. Fenstermacher,
M. E. Behrendsen,
and
C. Zahnow.
Characterization and expression of the complementary DNA encoding rat histidine decarboxylase.
Proc. Natl. Acad. Sci. USA
87:
733-737,
1990[Abstract].
41.
Lamberts, R.,
W. Creutzfeldt,
H. G. Struber,
G. Brunner,
and
E. Solcia.
Long-term omeprazole therapy in peptic ulcer disease: gastrin, endocrine cell growth, and gastritis.
Gastroenterology
104:
1356-1370,
1993[Medline].
42.
Larsson, H.,
E. Carlsson,
R. Hakanson,
H. Mattsson,
G. Nilsson,
R. Seensalu,
B. Wallmark,
and
F. Sundler.
Time-course of development and reversal of gastric endocrine cell hyperplasia after inhibition of acid secretion. Studies with omeprazole and ranitidine in intact and antrectomized rats.
Gastroenterology
95:
1477-1486,
1988[Medline].
43.
Larsson, H.,
E. Carlsson,
H. Mattsson,
L. Lundell,
F. Sundler,
G. Sundell,
B. Wallmark,
T. Watanabe,
and
R. Hakanson.
Plasma gastrin and gastric enterochromaffinlike cell activation and proliferation. Studies with omeprazole and ranitidine in intact and antrectomized rats.
Gastroenterology
90:
391-399,
1986[Medline].
44.
Lawrence, G. W.,
P. Foran,
and
J. O. Dolly.
Distinct exocytotic responses of intact and permeabilised chromaffin cells after cleavage of the 25-kDa synaptosomal-associated protein (SNAP-25) or synaptobrevin by botulinum toxin A or B.
Eur. J. Biochem.
236:
877-886,
1996[Abstract].
45.
Levius, O.,
N. Feinstein,
and
M. Linial.
Expression and localization of synaptotagmin I in rat parotid gland.
Eur. J. Cell Biol.
73:
81-92,
1997[Medline].
46.
Lindstrom, E.,
M. Bjorkqvist,
A. Boketoft,
D. Chen,
C. M. Zhao,
K. Kimura,
and
R. Hakanson.
Neurohormonal regulation of histamine and pancreastatin secretion from isolated rat stomach ECL cells.
Regul. Pept.
71:
73-86,
1997[Medline].
47.
Link, E.,
L. Edelmann,
J. H. Chou,
T. Binz,
S. Yamasaki,
U. Eisel,
M. Baumert,
T. C. Südhof,
H. Niemann,
and
R. Jahn.
Tetanus toxin action: inhibition of neurotransmitter release linked to synaptobrevin proteolysis.
Biochem. Biophys. Res. Commun.
189:
1017-1023,
1992[Medline].
48.
Liu, Y.,
D. Peter,
A. Roghani,
S. Schuldiner,
G. G. Prive,
D. Eisenberg,
N. Brecha,
and
R. H. Edwards.
A cDNA that suppresses MPP+ toxicity encodes a vesicular amine transporter.
Cell
70:
539-551,
1992[Medline].
49.
Lloyd, K. C.,
H. E. Raybould,
Y. Tache,
and
J. H. Walsh.
Role of gastrin, histamine, and acetylcholine in the gastric phase of acid secretion in anesthetized rats.
Am. J. Physiol.
262 (Gastrointest. Liver Physiol. 25):
G747-G755,
1992
50.
Loo, D. F.,
G. Sachs,
and
C. Prinz.
Potassium and chloride currents in rat gastric enterochromaffin-like cells.
Am. J. Physiol.
270 (Gastrointest. Liver Physiol. 33):
G739-G745,
1996.
51.
Lowe, A. W.,
L. Madeddu,
and
R. B. Kelly.
Endocrine secretory granules and neuronal synaptic vesicles have three integral membrane proteins in common.
J. Cell Biol.
106:
51-59,
1988[Abstract].
52.
Lundqvist, M.,
H. Arnberg,
J. Candell,
M. Malmgren,
E. Wilander,
L. Grimelius,
and
K. Oberg.
Silver stains for identification of neuroendocrine cells. A study of the chemical background.
Histochem. J.
22:
615-623,
1990[Medline].
53.
Mamune, S. R.,
K. Yamauchi,
Y. Tanno,
Y. Ohkawara,
H. Ohtsu,
D. Katayose,
K. Maeyama,
T. Watanabe,
S. Shibahara,
and
T. Takishima.
Functional analysis of alternatively spliced transcripts of the human histidine decarboxylase gene and its expression in human tissues and basophilic leukemia cells.
Eur. J. Biochem.
209:
533-539,
1992[Abstract].
54.
Navone, F.,
R. Jahn,
G. G. Di,
H. Stukenbrok,
P. Greengard,
and
P. De Camilli.
Protein p38: an integral membrane protein specific for small vesicles of neurons and neuroendocrine cells.
J. Cell Biol.
103:
2511-2527,
1986[Abstract].
55.
Neher, E.,
and
R. S. Zucker.
Multiple calcium-dependent processes related to secretion in bovine chromaffin cells.
Neuron
10:
21-30,
1993[Medline].
56.
Nylander, A. G.,
D. Chen,
I. Lilja,
J. Axelson,
I. Ihse,
J. F. Rehfeld,
F. Sundler,
and
R. Hakanson.
Enterochromaffin-like cells in rat stomach respond to short-term infusion of high doses of cholecystokinin but not to long-term, sustained, moderate hyperCCKemia caused by continuous cholecystokinin infusion or pancreaticobiliary diversion.
Scand. J. Gastroenterol.
28:
73-79,
1993[Medline].
57.
Olbe, L.,
C. Cederberg,
T. Lind,
and
M. Olausson.
Effect of omeprazole on gastric acid secretion and plasma gastrin in man.
Scand. J. Gastroenterol. Suppl.
166:
27-32,
1989[Medline].
58.
Pardee, A. B.
G1 events and regulation of cell proliferation.
Science
246:
603-608,
1989[Medline].
59.
Peng, X. R.,
X. B. Yao,
D. C. Chow,
J. G. Forte,
and
M. K. Bennett.
Association of syntaxin 3 and vesicle-associated membrane protein (VAMP) with H+/K+-ATPase-containing tubulovesicles in gastric parietal cells.
Mol. Biol. Cell
8:
399-407,
1997[Abstract].
60.
Penner, R.,
and
E. Neher.
The role of calcium in stimulus-secretion coupling in excitable and non-excitable cells.
J. Exp. Biol.
139:
329-345,
1988[Abstract].
61.
Peter, D.,
Y. Liu,
C. Sternini,
G. R. de,
N. Brecha,
and
R. H. Edwards.
Differential expression of two vesicular monoamine transporters.
J. Neurosci.
15:
6179-6188,
1995[Abstract].
62.
Prinz, C.,
M. Kajimura,
D. R. Scott,
F. Mercier,
H. F. Helander,
and
G. Sachs.
Histamine secretion from rat enterochromaffinlike cells.
Gastroenterology
105:
449-461,
1993[Medline].
63.
Prinz, C.,
N. Neumayer,
S. Mahr,
M. Classen,
and
W. Schepp.
Functional impairment of rat enterochromaffin-like cells by interleukin 1.
Gastroenterology
112:
364-375,
1997[Medline].
64.
Prinz, C.,
G. Sachs,
J. H. Walsh,
D. H. Coy,
and
S. V. Wu.
The somatostatin receptor subtype on rat enterochromaffinlike cells.
Gastroenterology
107:
1067-1074,
1994[Medline].
65.
Prinz, C.,
D. R. Scott,
D. Hurwitz,
H. F. Helander,
and
G. Sachs.
Gastrin effects on isolated rat enterochromaffin-like cells in primary culture.
Am. J. Physiol.
267 (Gastrointest. Liver Physiol. 30):
G663-G675,
1994
66.
Prinz, C.,
R. Zanner,
B. Höhne-Zell,
A. Galler,
M. Classen,
and
M. Gratzl.
Different histamine pools in rat gastric enterochromaffin-like cells (Abstract).
Gastroenterology
114:
A262,
1998.
67.
Ryberg, B.,
J. Axelson,
R. Hakanson,
F. Sundler,
and
H. Mattsson.
Trophic effects of continuous infusion of [Leu15]-gastrin-17 in the rat.
Gastroenterology
98:
33-38,
1990[Medline].
68.
Ryberg, B.,
Y. Tielemans,
J. Axelson,
E. Carlsson,
R. Hakanson,
H. Mattson,
F. Sundler,
and
G. Willems.
Gastrin stimulates the self-replication rate of enterochromaffinlike cells in the rat stomach. Effects of omeprazole, ranitidine, and gastrin-17 in intact and antrectomized rats.
Gastroenterology
99:
935-942,
1990[Medline].
69.
Sachs, G.,
and
C. Prinz.
Gastric enterochromaffin-like cells and the regulation of acid secretion.
News Physiol. Sci.
11:
57-62,
1996.
70.
Sachs, G.,
C. Prinz,
D. Loo,
K. Bamberg,
M. Besancon,
and
J. M. Shin.
Gastric acid secretion: activation and inhibition.
Yale J. Biol. Med.
67:
81-95,
1994[Medline].
71.
Sachs, G.,
J. M. Shin,
K. Bamberg,
and
C. Prinz.
Gastric acid secretion. The H,K-ATPase and ulcer disease.
In: Molecular Biology of Membrane Transport Disorders, edited by S. G. Schultz,
T. E. Andreoli,
and A. M. Brown. New York: Plenum, 1996, p. 469-483.
72.
Sachs, G.,
N. X. Zeng,
and
C. Prinz.
Physiology of isolated gastric endocrine cells.
Annu. Rev. Physiol.
59:
243-256,
1997[Medline].
73.
Sakai, H.,
Y. Tabuchi,
B. Kakinoki,
H. Seike,
S. Kumagai,
C. Matsumoto,
and
N. Takeguchi.
Ca2+-activated outward-rectifier K+ channels and histamine release by rat gastric enterochromaffin-like cells.
Eur. J. Pharmacol.
291:
153-158,
1995[Medline].
74.
Schiavo, G.,
F. Benfenati,
B. Poulain,
O. Rossetto,
L. P. Polverino-de,
B. R. DasGupta,
and
C. Montecucco.
Tetanus and botulinum-B neurotoxins block neurotransmitter release by proteolytic cleavage of synaptobrevin.
Nature
359:
832-835,
1992[Medline].
75.
Schilling, K.,
and
M. Gratzl.
Quantification of p38/synaptophysin in highly purified adrenal medullary chromaffin vesicles.
FEBS Lett.
233:
22-24,
1988[Medline].
76.
Scott, D. R.,
S. J. Hersey,
C. Prinz,
and
G. Sachs.
Actions of antiulcer drugs.
Science
262:
1453-1454,
1993[Medline].
77.
Shin, J. M.,
M. Besancon,
C. Prinz,
A. Simon,
and
G. Sachs.
Continuing development of acid pump inhibitors: site of action of pantoprazole.
Aliment. Pharmacol. Ther. 8 Suppl.
1:
11-23,
1994.
78.
Simonsson, M.,
S. Eriksson,
R. Hakanson,
T. Lind,
H. Lonroth,
L. Lundell,
D. T. O'Connor,
and
F. Sundler.
Endocrine cells in the human oxyntic mucosa. A histochemical study.
Scand. J. Gastroenterol.
23:
1089-1099,
1988[Medline].
79.
Solcia, E.,
G. Rindi,
N. Havu,
and
G. Elm.
Qualitative studies of gastric endocrine cells in patients treated long-term with omeprazole.
Scand. J. Gastroenterol. Suppl.
166:
129-137,
1989[Medline].
80.
Soll, A. H.
Mechanisms of action of antisecretory drugs. Studies on isolated canine fundic mucosal cells.
Scand. J. Gastroenterol. Suppl.
125:
1-8,
1986[Medline].
81.
Soll, A. H.,
M. Toomey,
D. Culp,
F. Shanahan,
and
M. A. Beaven.
Modulation of histamine release from canine fundic mucosal mast cells.
Am. J. Physiol.
254 (Gastrointest. Liver Physiol. 17):
G40-G48,
1988
82.
Südhof, T. C.
The synaptic vesicle cycle: a cascade of protein-protein interactions.
Nature
375:
645-653,
1995[Medline].
83.
Taguchi, Y.,
T. Watanabe,
H. Kubota,
H. Hayashi,
and
H. Wada.
Purification of histidine decarboxylase from the liver of fetal rats and its immunochemical and immunohistochemical characterization.
J. Biol. Chem.
259:
5214-5221,
1984
84.
Tielemans, Y.,
D. Chen,
F. Sundler,
R. Hakanson,
and
G. Willems.
Reversibility of the cell kinetic changes induced by omeprazole in the rat oxyntic mucosa. An autoradiographic study using tritiated thymidine.
Scand. J. Gastroenterol.
27:
155-160,
1992[Medline].
85.
Tielemans, Y.,
R. Hakanson,
F. Sundler,
and
G. Willems.
Proliferation of enterochromaffin-like cells in omeprazole-treated hypergastrinemic rats.
Gastroenterology
96:
723-729,
1989[Medline].
86.
Tielemans, Y.,
G. Willems,
F. Sundler,
and
R. Hakanson.
Self-replication of enterochromaffin-like cells in the mouse stomach.
Digestion
45:
138-146,
1990[Medline].
87.
Uceda, G.,
A. R. Artalejo,
M. G. Lopez,
F. Abad,
E. Neher,
and
A. G. Garcia.
Ca2+-activated K+ channels modulate muscarinic secretion in cat chromaffin cells.
J. Physiol. (Lond.)
454:
213-230,
1992[Abstract].
88.
Wallmark, B.,
I. Skanberg,
H. Mattsson,
K. Andersson,
F. Sundler,
R. Hakanson,
and
E. Carlsson.
Effect of 20 weeks' ranitidine treatment on plasma gastrin levels and gastric enterochromaffin-like cell density in the rat.
Digestion
45:
181-188,
1990[Medline].
89.
Wank, S. A.
Cholecystokinin receptors.
Am. J. Physiol.
269 (Gastrointest. Liver Physiol. 32):
G628-G646,
1995
90.
Wank, S. A.,
J. R. Pisegna,
and
A. de Weerth.
Brain and gastrointestinal cholecystokinin receptor family: structure and functional expression.
Proc. Natl. Acad. Sci. USA
89:
8691-8695,
1992[Abstract].
91.
Watson, F.,
D. G. Deavall,
J. A. Macro,
R. Kiernan,
and
R. Dimaline.
Transcriptional activation of vesicular monoamine transporter 2 in the pre-B cell line Ea3.123.
Biochem. J.
337:
193-199,
1999[Medline].
92.
Weihe, E.,
M. K. Schafer,
J. D. Erickson,
and
L. E. Eiden.
Localization of vesicular monoamine transporter isoforms (VMAT1 and VMAT2) to endocrine cells and neurons in rat.
J. Mol. Neurosci.
5:
149-164,
1994[Medline].
93.
Wiedenmann, B.,
H. Rehm,
M. Knierim,
and
C. M. Becker.
Fractionation of synaptophysin-containing vesicles from rat brain and cultured PC12 pheochromocytoma cells.
FEBS Lett.
240:
71-77,
1988[Medline].
94.
Wilander, E.
Diagnostic pathology of gastrointestinal and pancreatic neuroendocrine tumours.
Acta Oncol.
28:
363-369,
1989[Medline].
95.
Yamamoto, J.,
T. Fukui,
K. Suzuki,
S. Tanaka,
K. Yatsunami,
and
A. Ichikawa.
Expression and characterization of recombinant mouse mastocytoma histidine decarboxylase.
Biochim. Biophys. Acta
1216:
431-440,
1993[Medline].
96.
Zeng, N.,
T. Kang,
R. M. Lyu,
H. Wong,
Y. Wen,
J. H. Walsh,
G. Sachs,
and
J. R. Pisegna.
The pituitary adenylate cyclase activating polypeptide type 1 receptor (PAC1-R) is expressed on gastric ECL cells: evidence by immunocytochemistry and RT-PCR.
Ann. NY Acad. Sci.
865:
147-156,
1998
97.
Zeng, N.,
T. Kang,
Y. Wen,
H. Wong,
J. Walsh,
and
G. Sachs.
Galanin inhibition of enterochromaffin-like cell function.
Gastroenterology
115:
330-339,
1998[Medline].
98.
Zhao, C. M.,
G. Jacobsson,
D. Chen,
R. Hakanson,
and
B. Meister.
Exocytotic proteins in enterochromaffin-like (ECL) cells of the rat stomach.
Cell Tissue Res.
290:
539-551,
1997[Medline].