Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01350 (gastrin)
 9,683 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The enzyme L-histidine decarboxylase (HDC; EC 4.1.1.22), which converts L-histidine to histamine, plays a key role in the regulation of acid secretion. In the rat and human stomach, the peptide hormone gastrin appears to be one of the main regulators of HDC expression. In rats, marked elevation of gastric HDC mRNA abundance was observed within 12 h after induction of hypergastrinemia by a single injection of the proton-pump blocker omeprazole. In situ hybridization revealed that HDC expression occurred in the basal third of gastric glands where enterochromaffin-like cells are localized. To study the regulation of HDC gene transcription, 1,291 nucleotides of the 5'-flanking region of the rat HDC gene and the noncoding portion of exon 1 were cloned and sequenced. Gastrin and cholecystokinin (CCK) octapeptide equipotently stimulated the transcriptional activity of the rat HDC promoter three- to fourfold, and deletion analysis revealed the presence of a gastrin response element within 201 nucleotides upstream of the translational start site. Time-course studies revealed maximal activation of the HDC promoter after 12-36 h. Direct stimulation of protein kinase C (PKC) with the phorbol ester phorbol 12-myristate 13-acetate (PMA) substantially elevated rat HDC promoter activity, whereas induction of Ca2+ -dependent signaling pathways with thapsigargin was without effect. Downregulation or blockade of PKC abolished the effects of gastrin and PMA on the HDC promoter. These data indicate that stimulation of the CCK-B/gastrin receptor activates the rat HDC promoter in a time- and dose-dependent fashion and that this effect is primarily mediated via a PKC-dependent signaling pathway. Use of HDC as a model gene will allow further investigation of the intracellular pathways that are involved in gastrin-dependent gene regulation.
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PMID:Rat histidine decarboxylase promoter is regulated by gastrin through a protein kinase C pathway. 892 92

Histamine is a biogenic amine, which is involved in a variety of biologic processes comprising inflammation, allergic responses, neurotransmission and regulation of gastric acid secretion. The key enzyme for the generation of histamine is histidine decarboxylase (HDC), which converts the amino acid L-histidine to histamine. In this article, we review the history, biochemistry and molecular biology of this enzyme. Northern blot studies in rats demonstrated that HDC gene expression in the stomach and liver are developmentally regulated with highest levels of expression in the late fetal state, indicating a role of the gene in growth and development. In the stomach of adult rats, HDC mRNA levels are elevated after omeprazole-induced hypergastrinemia, and in situ hybridization showed that expression of HDC is restricted to the glandular area in which ECL cells are located. Since no permanent ECL cell line is at hand for in vitro studies, we established a suitable cell system by stable transfection of a human gastric adenocarcinoma cell line (AGS) with the CCK-B/gastrin receptor. Transfection of this AGS-B cell line with reporter gene constructs comprising 5'-flanking DNA sequence of the HDC gene joined to the firefly luciferase gene revealed transcriptional regulation of the HDC promoter by gastrin through a protein-kinase C-dependent pathway. Taken together, these studies are consistent with the concept of HDC transcriptional regulation as at least one phase of the overall response to gastrin.
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PMID:The regulation of histidine decarboxylase gene expression. 904 86

In this study we investigated the short-term effect of somatostatin on histamine synthesis in a cell population isolated from rabbit gastric mucosa and enriched in enterochromaffin-like cells. Somatostatin inhibited basal and gastrin-stimulated histamine synthesis through a dual mechanism involving a decrease in the affinity of histidine decarboxylase (HDC) for its substrate (L-histidine) and a reduction in the number of functional HDC molecules. H-89 (an inhibitor of cAMP-dependent protein kinase) mimicked somatostatin-induced reduction of HDC affinity, which, on the contrary, was selectively reversed by pertussis toxin (PTX). Furthermore, forskolin was shown to reverse the inhibitory effect of H-89 and to prevent the somatostatin-induced reduction in HDC affinity for L-histidine. Thus, the somatostatin-induced reduction in affinity seems to involve a PTX-sensitive G protein and an inhibition of the cAMP-dependent pathway. On the other hand, the somatostatin-induced decrease in the number of functional HDC molecules seems to be PTX insensitive and independent from a modulation of the cAMP pathway, and does not seem to involve a significant change in HDC messenger RNA expression or a regulation of protein kinase C. The exact nature of this second mechanism will need further studies to be elucidated.
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PMID:Short-term inhibitory effect of somatostatin on gastric histamine synthesis. 904 95

Prostaglandins (PGs) affect various aspects of gastric functions. In the present study the orally administered PGI2 derivative beraprost sodium (TRK-100.1 micrograms per kg body weight) decreased oxyntic histidine decarboxylase activity without changing serum gastrin levels. Antral pH increased 4 hr after treatment. Beraprost also decreased the pentagastrin-induced histidine decarboxylase activity at the same dose. Serum levels of secretin, somatostatin and glucose, and oxyntic mucosal levels of histamine and somatostatin, showed no significant change after treatment with beraprost. These results suggest that the response of oxyntic histidine decarboxylase to gastrin is modified by one or more prostanoids including PGI2. This mechanism might play a role in gastric mucosal protection.
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PMID:Suppression of histidine decarboxylase activity in rat oxyntic mucosa by beraprost sodium, a prostacyclin analogue. 906 65

Recently, we showed that the ECL cells in the oxyntic mucosa of the rat stomach are an important source of circulating pancreastatin, a fragment of chromogranin A. The present study examined how much the ECL cells contribute to the circulating levels of pancreastatin during omeprazole-evoked hypergastrinemia. Rats received omeprazole (400 mumol kg-1 day-1) by the oral route for 3 weeks. Two weeks after the start of the treatment, the rats were subjected to a sham operation or fundectomy. The concentrations of gastrin and pancreastatin in serum were monitored before and after the operations. The ECL cells were visualized by pancreastatin immunostaining and their number was determined. The activity of oxyntic mucosal histidine decarboxylase (HDC) was measured before and after 2 weeks of omeprazole treatment. Omeprazole-induced hypergastrinemia resulted in elevated serum pancreastatin and increased oxyntic mucosal HDC activity. Pancreastatin-immunoreactive cells were equally numerous before and after 2 weeks of omeprazole treatment. After surgical removal of the ECL cells by fundectomy, the serum gastrin concentration remained high whereas the serum pancreastatin concentration decreased by 90%. We conclude that the ECL cells in omeprazole-treated rats are responsible for 90% of circulating pancreastatin.
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PMID:Evidence that rat stomach ECL cells represent the main source of circulating pancreastatin. 910 Feb 84

The histidine decarboxylase (HDC) gene is regulated transcriptionally by gastrin and phorbol 12-myristate 13-acetate (PMA) through a protein kinase C (PKC)-related pathway. To determine the role of AP-1 (fos/jun) in the regulation of the HDC promoter, gastric cancer (AGS-B) cells stably expressing the cholecystokinin-B/ gastrin receptor and the 1.8-kb human (h) HDC-luciferase (luc) construct were cotransfected with constructs expressing c-fos and c-jun. Overexpression of c-fos and c-jun activated the HDC promoter in a dose-dependent fashion in 1.8-kb hHDC-luc/AGS-B cells as well as in transfected F9 embryonal carcinoma cells, which lack endogenous AP-1 activity. PMA was unable to activate the HDC promoter in F9 cells, which were not transfected with c-fos and c-jun. Gastrin stimulation increased c-fos and c-jun mRNA abundance and AP-1-dependent transcriptional activity, as assessed by a reporter construct in which the CAT reporter gene is under the control of a 12-O-tetradecanoylphorbol-13-acetate response element multimer. Gastrin-stimulated HDC promoter activity was blocked by transfection of c-fos antisense and dominant negative c-jun expression constructs. Finally, overexpression of c-fos and c-jun activated the hHDC promoter through a downstream cis-acting element (gastrin response element), which does not bind AP-1. In conclusion, activation of AP-1 is essential for gastrin-stimulated HDC transcription, but the mechanism appears to be indirect.
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PMID:Gastrin regulates the human histidine decarboxylase promoter through an AP-1-dependent mechanism. 914 14

Gastrin controls the histamine- and chromogranin A-producing enterochromaffin-like (ECL) cells, the predominant endocrine cell population in the acid-producing part of the rat stomach. They are responsible for most of the circulating pancreastatin, a chromogranin A-derived peptide. The present study examines the ability of two potent and highly selective cholecystokinin-B/gastrin receptor antagonists, RP73870 and YM022, to incapacitate the ECL cells. The two antagonists were given by continuous subcutaneous infusion to otherwise untreated rats and to hypergastrinaemic rats treated with gastrin-17 (continuous subcutaneous infusion) or omeprazole (orally) for 7 days. Several parameters reflecting ECL cell activity were measured: The oxyntic mucosal histidine decarboxylase activity, the histamine concentration, the histidine decarboxylase mRNA and chromogranin A mRNA concentrations, and the serum pancreastatin concentration. In addition, the serum gastrin concentration was measured. RP73870 and YM022 greatly lowered the oxyntic mucosal histidine decarboxylase activity and the histidine decarboxylase mRNA and chromogranin A mRNA concentrations, and also reduced the oxyntic mucosal histamine concentration and the serum pancreastatin concentration. Moreover, they raised the serum gastrin concentration. With respect to blockade of histidine decarboxylase activity, 1.0 mumol.kg-1.hr-1 was an almost maximally effective dose for both RP73870 and YM022. The corresponding ID50 values were 0.04 and 0.05 mumol.kg-1.hr-1. RP73870 and YM022 inhibited the hypergastrinaemia-evoked rise in all ECL-cell parameters. The results suggest that sustained cholecystokinin-B/gastrin receptor blockade causes lasting deactivation of the ECL cells.
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PMID:Cholecystokinin-B/gastrin receptor blockade suppresses the activity of rat stomach ECL cells. 925 80

The ECL cells constitute the predominant endocrine cell population in the mucosa of the acid-secreting part of the stomach (fundus). They are rich in chromogranin A (CGA), histamine and histidine decarboxylase (HDC). They secrete CGA-derived peptides and histamine in response to gastrin. The objective of this investigation was to examine the expression of pancreastatin (rat CGA266-314) and WE14 (rat CGA343-356) in rat stomach ECL cells. The distribution and cellular localisation of pancreastatin- and WE14-like immunoreactivities (LI) were analysed by radioimmunoassay and immunohistochemistry with antibodies against pancreastatin, WE14 and HDC. The effect of food deprivation on circulating pancreastatin-LI was examined in intact rats and after gastrectomy or fundectomy. Rats received gastrin-17 (5 nmol/kg/h) by continuous intravenous infusion or omeprazole (400 micromol/kg) once daily by the oral route, to induce hypergastrinemia. CGA-derived peptides in the ECL cells were characterised by gel permeation chromatography. The expression of CGA mRNA was examined by Northern blot analysis. Among all of the endocrine cells in the body, the ECL cell population was the richest in pancreastatin-LI, containing 20-25% of the total body content. Food deprivation and/or surgical removal of the ECL cells lowered the level of pancreastatin-LI in serum by about 80%. Activation of the ECL cells by gastrin infusion or omeprazole treatment raised the serum level of pancreastatin-LI, lowered the concentrations of pancreastatin- and WE14-LI in the ECL cells and increased the CGA mRNA concentration. Chromatographic analysis of the various CGA immunoreactive components in the ECL cells of normal and hypergastrinemic rats suggested that these cells respond to gastrin with a preferential release of the low-molecular-mass forms.
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PMID:Expression of the chromogranin A-derived peptides pancreastatin and WE14 in rat stomach ECL cells. 927 24

1. Secretion of the antral hormone gastrin is increased by protein in the gastric lumen and by nervous reflexes. We have examined the relative importance of luminal and neuronal mechanisms, by lesioning the antral innervation using benzalkonium chloride. 2. Benzalkonium chloride was applied to the serosa of the antrum in anaesthetized rats. In some animals, a stainless-steel cannula was also implanted in the corpus. Animals were allowed 10 days to recover. Plasma gastrin was measured by radioimmunoassay and mRNAs encoding gastrin, somatostatin and histidine decarboxylase were measured by Northern blot. 3. Antral denervation was associated with gastric retention after fasting, and elevated plasma gastrin (28.4 +/- 7 pM compared with 7.6 +/- 1.0 pM in controls). When fasted control or denervated rats were refed, plasma gastrin increased 3-fold in both cases. A gastrin-releasing peptide antagonist inhibited the post-prandial rise in plasma gastrin in control rats, but had no effect in antrally denervated rats. 4. In fasted, antrally denervated rats with a gastric fistula, basal gastric acid secretion was depressed 3-fold, and plasma gastrin concentrations were similar to controls. 5. Distension of the stomach with peptone via a barostat attached to the gastric cannula (5 cm H2O, 30 min), produced 3-fold increases in plasma gastrin in both control and denervated rats. However, distension with a non-nutrient solution at pH 6.0 had no effect in controls, but increased gastrin to a similar extent to peptone in denervated rats; distension with 50 mM HCl had no effect in either control or denervated rats. 6. Somatostatin and gastrin mRNA abundances in the antrum were depressed by about 35% by antral denervation, but somatostatin mRNA in the corpus was unchanged; GAPDH mRNA abundance was unaffected by antral denervation. 7. The data suggest that luminal nutrient releases gastrin in the rat, in vivo, via activation of antral neurons secreting gastrin-releasing peptide, and that the antral innervation normally inhibits G-cell responses to non-nutrient distension of the stomach. After antral denervation, gastric distension with a non-nutrient solution is an adequate stimulus for gastrin release.
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PMID:Increased sensitivity of gastrin cells to gastric distension following antral denervation in the rat. 928 84

1 The so-called enterochromaffin-like (ECL) cells constitute 65-75% of the endocrine cells in the acid-producing part of the rat stomach. They produce and secrete histamine and pancreastatin, a chromogranin A (CGA)-derived peptide, in response to gastrin, Cholecystokinin (CCK)B/gastrin receptor blockade is known to suppress their activity. 2 We have examined the time course of the deactivation of the ECL cells following treatment with the selective CCKB receptor antagonists RP73870 and YM022. The drugs were given by continuous subcutaneous infusion for a time span of 1 h to 3 weeks and the serum gastrin concentration and various ECL cell parameters were measured (oxyntic mucosal histidine decarboxylase (HDC) activity, histamine and pancreastatin concentrations, HDC mRNA and CGA mRNA levels, and circulating pancreastatin concentration). 3 The two antagonists caused a prompt and dramatic decline in the oxyntic mucosal HDC activity and HDC mRNA level. The HDC activity started to decline after 1-2 h, was reduced by 60-70% after 6 h and was maximally suppressed (80-90%) after 24-48 h. The HDC mRNA level was reduced after 12 h and was at about 20% of the pretreatment level after 2-4 days of infusion. The ECL cell histamine concentration was lowered by about 50% after 7-10 days. 4 RP73870 and YM022 lowered the serum pancreastatin concentration and the oxyntic mucosal CGA mRNA level. The serum pancreastatin concentration was reduced by 40% after 6 h and the reduction was maximal after 2-3 days. A decline in the oxyntic mucosal CGA mRNA level was noted after 12 h with a maximal reduction after 2-4 days of infusion. The ECL cell pancreastatin concentration was reduced by 30-40% after 3 weeks. 5 The infusion of RP73870 and YM022 induced hypergastrinaemia. The serum gastrin concentration started to rise after 2-4 h, there was a 2 fold increase after 6 h and maximal increase (3-4 fold) after 2-3 days of treatment. 6 In conclusion, CCKB/gastrin receptor blockade promptly deactivates the ECL cells. Deactivation, manifested in a greatly reduced HDC activity, was apparent after 1-2 h of the infusion. The serum pancreastatin concentration and the oxyntic mucosal HDC mRNA and CGA mRNA levels were greatly reduced after 1-2 days. The ECL cell concentrations of histamine and pancreastatin declined quite slowly by comparison.
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PMID:Time-course of deactivation of rat stomach ECL cells following cholecystokinin B/gastrin receptor blockade. 929 21


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