UNIPROT:P01350 - FACTA Search

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Query: UNIPROT:P01350 (gastrin)
9,683 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

We have previously observed that gastrin has a cholecystokinin B (CCK-B) receptor-mediated growth-promoting effect on the AR42J rat pancreatic acinar cell line and that this effect is paralleled by induction of expression of the early response gene c-fos. We undertook these experiments to elucidate the mechanism for induction of c-fos and the linkage of this action to the trophic effects of gastrin. Gastrin (0.1-10 nM) dose dependently induced luciferase activity in AR42J cells transfected with a construct consisting of a luciferase reporter gene coupled to the serum response element (SRE) of the c-fos promoter. This effect was blocked by the specific CCK-B receptor antagonist D2 but not by the specific CCK-A receptor antagonist L-364,718 or by pertussis toxin, indicating that gastrin targets the SRE via specific CCK-B receptors through a mechanism independent of Gi. Inhibition of protein kinase C (PKC) either by prolonged (24 h) exposure of the cells to the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (100 nM) or by incubation with the selective inhibitor GF-109203X (3.5 microM) resulted in an 80% reduction in luciferase activity. Similar results were observed in the presence of the specific extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitor PD-98059 (50 microM). We measured ERK2 activity in AR42J cells via in-gel kinase assays and observed that gastrin (1 pM-100 nM) induced ERK2 enzyme activity in a dose-dependent manner. Addition of GF-109203X and PD-98059, either alone or in combination, produced, respectively, partial and total inhibition of gastrin-induced ERK2 activity. Gastrin induction of ERK2 activity also resulted in a threefold increase in the transcriptional activity of Elk-1, a factor known to bind to the c-fos SRE and to be phosphorylated and activated by ERK2. PD-98059 blocked the growth-promoting effect of gastrin on the AR42J cells, demonstrating that this effect depends on activation of MEK. Our data lead us to conclude that the trophic actions of gastrin are mediated by ERK2-induced c-fos gene expression via PKC-dependent and -independent pathways.
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PMID:Molecular mechanisms for the growth factor action of gastrin. 935 32

We have previously reported that gastrin induces a rapid and transient tyrosine phosphorylation of phospholipase C gamma 1 (PLC gamma 1) in association with inositol 1,4,5-trisphosphate (IP3) formation in rat colonic epithelial cells (34). In this study, we demonstrate that gastrin regulates IP3 formation mainly through PLC gamma 1 isozyme. Immunoblotting analysis revealed the expression of PLC beta 3 and -gamma 1, but not PLC beta 1, -beta 2, or -beta 4 in the rat colonic epitheliums. To explore what PLC isozyme(s) modulates gastrin effect on IP3, immunoneutralizing antibody to PLC beta 1, -beta 3, or -gamma 1 was introduced into the colonic cells using a lipid carrier. The gastrin-stimulated increase in IP3 concentration was specifically prevented by anti-PLC gamma 1 but not by anti-PLC beta 1 or -beta 3 antibody. Immunoprecipitation assays have also revealed that gastrin promoted an increase in tyrosine phosphorylation and co-precipitation of a 60 kDa src kinase with PLC gamma 1. Administration of antibody specific to pp60c-src into the colonic cells prevented the gastrin-stimulated increases in IP3. Tyrosine phosphorylation of PLC gamma 1 may be a major mechanism through which gastrin regulates IP3 level in the colonic cells. Pretreatment of cells with the tyrosine kinase inhibitor genistein abrogated gastrin's effect on IP3, while extended pretreatment with pertussis toxin, a G-protein inhibitor, did not affect the ability of gastrin to stimulate IP3 formation. Colonic cells expressed the G alpha i subunits1-3; however, immunoblotting analysis did not reveal any difference in G alpha i proteins' expression between control and gastrin treated cells. The results provide direct evidence that gastrin regulates IP3 level by a signaling mechanism that involves PLC gamma 1 and pp60c-src kinase.
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PMID:Gastrin induces IP3 formation through phospholipase C gamma 1 and pp60c-src kinase. 943 36

Nerve fibers containing bombesin (BB)/gastrin-releasing polypeptide (GRP), pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal polypeptide (VIP), or galanin are known to innervate the mucosa of the upper small intestine. Both BB/GRP and PACAP have been shown to elicit secretin secretion in vivo. We studied whether the above-mentioned neuropeptides can act directly on secretin-producing cells, including the murine neuroendocrine cell line STC-1 and a secretin cell-enriched preparation isolated from rat upper small intestinal mucosa. Secretin release from both cell types was stimulated by various agents known to elicit secretin release and by the neuropeptides BB, GRP, and PACAP, suggesting a comparable response between the two cell preparations. The effects of neuropeptides were further studied in STC-1 cells. BB, GRP, and PACAP stimulated secretin release time and concentration dependently. VIP also stimulated secretin release concentration dependently. Stimulation by BB/GRP or PACAP was accompanied by elevation of inositol-1,4,5-trisphosphate (IP3) or cAMP, respectively. The stimulatory effect of PACAP on secretin release was synergistically enhanced by BB without any synergistic increase in IP3 or cAMP production, suggesting cross talk between different signal transduction pathways downstream of the production of these two second messengers. The L-type Ca2+ channel blocker diltiazem (10 microM) and the Ca2+ chelator EGTA (1 mM) significantly inhibited BB-stimulated secretin release by 64% and 59%, respectively, and inhibited PACAP-stimulated release by 75% and 55%, respectively. The protein kinase A-specific inhibitor Rp-cAMPS (100 microM) also inhibited both BB- and PACAP-stimulated secretin release by 30% and 62%, respectively. Galanin inhibited BB- and PACAP-stimulated secretin release and production of second messengers in a concentration-dependent and pertussis toxin-sensitive manner. These results suggested that the neuropeptides BB/GRP, PACAP, VIP, and galanin can modulate secretin release in secretin-producing cells and that STC-1 cells can serve as a useful model for studying the cellular mechanism of secretin secretion elicited by luminal secretagogues and neuropeptides.
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PMID:Modulation of secretin release by neuropeptides in secretin-producing cells. 968 45

1. The present study examines the effect of naturally occurring prostanoids and prostaglandin (PG) congeners on gastrin- and pituitary adenylate cyclase-activating peptide (PACAP)-evoked histamine and pancreastatin secretion from isolated rat stomach ECL cells. 2. ECL cells (75-85% purity) were isolated from rat stomach using pronase digestion followed by repeated counter-flow elutriation and cultured for 48 h before secretion experiments. The release of histamine and pancreastatin was determined by radioimmunoassay. 3. None of the PGs tested stimulated the release of either histamine or pancreastatin. 4. PGE1 and PGE2 inhibited both gastrin- and PACAP-evoked histamine and pancreastatin secretion (IC50 = 1-2 x 10(-10) M). Most other naturally occuring prostanoids and PG congeners had no or little inhibitory effect. The PGE analogues misoprostol and sulprostone were more potent (IC50 = 0.9 x 10(-11) M and 2 x 10(-11) M respectively) than PGE1 and PGE2. The rank order of potency was misoprostol > sulprostone > PGE1 = PGE2, suggesting the involvement of the so-called EP3 receptor. 5. The effects of PGs on the stomach ECL cells may be direct or indirect, for instance through the stimulated release of somatostatin from contaminating D cells (2-3%). However, the amount of somatostatin in the cell culture after 48 h was below the limit of detection, and somatostatin immunoneutralization did not prevent misoprostol from inhibiting secretion from the ECL cells. 6. The misoprostol-induced inhibition was reversed by pertussis toxin suggesting the involvement of G-protein subunits G alpha(0) and/or G alpha(i). 7. In view of the potency by which PGE1, PGE2, misoprostol and sulprostone inhibited the stimulated release of histamine and pancreastatin, we suggest that the ECL cells represent a primary target for prostaglandins acting via an EP3 receptor in the oxyntic mucosa. 8. The results suggest that the clinically useful effect of misoprostol as an anti-ulcer drug reflects its ability to inhibit stomach ECL-cell histamine secretion.
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PMID:Prostaglandins inhibit secretion of histamine and pancreastatin from isolated rat stomach ECL cells. 972 Aug 5

Peptides release histamine from enterochromaffin-like (ECL) cells because of elevation of intracellular Ca(2+) concentration ([Ca(2+)](i)) by either receptor-operated or voltage-dependent Ca(2+) channels (VDCC). To determine whether VDCCs contribute to histamine release stimulated by gastrin or pituitary adenylate cyclase-activating polypeptide (PACAP), the presence of VDCCs and their possible modulation by peptides was investigated in a 48-h cultured rat gastric cell population containing 85% ECL cells. Video imaging of fura 2-loaded cells was used to measure [Ca(2+)](i), and histamine was assayed by RIA. Cells were depolarized by increasing extracellular K(+) concentrations or by 20 mM tetraethylammonium (TEA(+)). Cell depolarization increased transient and steady-state [Ca(2+)](i) and resulted in histamine release, dependent on extracellular Ca(2+). These K(+)- or TEA(+)-dependent effects on histamine release from ECL cells were coupled to activation of parietal cells in intact rabbit gastric glands, and L-type channel blockade by 2 microM nifedipine inhibited 50% of [Ca(2+)](i) elevation and histamine release. N-type channel blockade by 1 microM omega-conotoxin GVIA inhibited 25% of [Ca(2+)](i) elevation and 14% of histamine release. Inhibition was additive. The effects of 20 mM TEA(+) were fully inhibited by 2 microM nifedipine. Both classes of Ca(2+) channels were found in ECL cells, but not in parietal cells, by RT-PCR. Nifedipine reduced PACAP-induced (but not gastrin-stimulated) Ca(2+) entry and histamine release by 40%. Somatostatin, peptide YY (PYY), and galanin dose dependently inhibited L-type Ca(2+) channels via a pertussis toxin-sensitive pathway. L-type VDCCs play a role in PACAP but not gastrin stimulation of histamine release from ECL cells, and the channel opening is inhibited by somatostatin, PYY, and galanin by interaction with a G(i) or G(o) protein.
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PMID:Role of neuropeptide-sensitive L-type Ca(2+) channels in histamine release in gastric enterochromaffin-like cells. 1060 Aug 25

Peptide YY (PYY) released postprandially from the ileum and colon displays a potent inhibition of cephalic and gastric phases of gastric acid secretion through both central and peripheral mechanisms. To modulate vagal regulation of gastric functions, circulating PYY enters the brain through the area postrema and the nucleus of the solitary tract, where it exerts a stimulatory action through PYY-preferring Y1-like receptors, and an inhibitory action through Y2 receptors. In the gastric mucosa, PYY binds to Y1 receptors in the enterochromaffin-like cells to inhibit gastrin-stimulated histamine release and calcium signaling via a pertussis toxin-sensitive pathway.
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PMID:Central and peripheral regulation of gastric acid secretion by peptide YY. 1182 49

Described in this report is a successful cloning and characterization of a functionally active Drosophila sulfakinin receptor designated DSK-R1. When expressed in mammalian cells, DSK-R1 was activated by a sulfated, Met(7-->Leu(7)-substituted analog of drosulfakinin-1, FDDY(SO(3)H)GHLRF-NH(2) ([Leu(7)]-DSK-1S). The interaction of [Leu(7)]-DSK-1S with DSK-R1 led to a dose-dependent intracellular calcium increase with an EC(50) in the low nanomolar range. The observed Ca(2+) signal predominantly resulted from activation of pertussis toxin (PTX)-insensitive signaling pathways pointing most likely to G(q/11) involvement in coupling to the activated receptor. The unsulfated [Leu(7)]-DSK-1 was ca. 3000-fold less potent than its sulfated counterpart which stresses the importance of the sulfate moiety for the biological activity of drosulfakinin. The DSK-R1 was specific for the insect sulfakinin since two related vertebrate sulfated peptides, human CCK-8 and gastrin-II, were found inactive when tested at concentrations up to 10(-5) M. To our knowledge, the cloned DSK-R1 receptor is the first functionally active Drosophila sulfakinin receptor reported to date.
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PMID:Cloning and functional expression of the first Drosophila melanogaster sulfakinin receptor DSK-R1. 1184 6

The existence of an osteotropic hormone (referred to as gastrocalcin) in the ECL cells of the gastric mucosa has been suggested. Both gastrin and an extract of the oxyntic mucosa lower blood Ca(2+) and stimulate Ca(2+) uptake into bone. The ECL cells are known to operate under gastrin control and, conceivably, gastrin lowers blood Ca(2+) indirectly by releasing the hypothetical ECL cell hormone. We have shown earlier that extracts of isolated ECL cells or of the granule/vesicle fraction of the oxyntic mucosa evoke a typical Ca(2+)-mediated second messenger response in osteoblastic cells. In the present study, we characterize this response further. An increase in intracellular inositol 1,4,5-trisphosphate (IP(3)) concentration was observed after treatment of UMR-106.01 osteoblast-like cells with extracts of ECL cells or granule/vesicle-enriched fractions from oxyntic mucosa. Intracellular cyclic adenosine monophosphate (cAMP) concentrations were not affected. Inhibition of phospholipase C (PLC) by U-73122 abolished the increase in [Ca(2+)](i). Preincubation of UMR-106.01 cells with pertussis toxin, which blocks many G-proteins, did not prevent the increases in IP(3) and [Ca(2+)](i). It was also found that the novel peptide hormone ghrelin, produced in the A-like cells of the oxyntic mucosa, did not evoke any Ca(2+) signal in osteoblastic cells. The results indicate that the extracts mediate their effects through a pertussis toxin-insensitive mechanism, and that binding to a receptor leads to activation of PLC and production of IP(3) resulting in increased [Ca(2+)](i). The putative osteotropic hormone is distinct from ghrelin.
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PMID:Effects of ECL cell extracts and granule/vesicle-enriched fractions from rat oxyntic mucosa on cAMP and IP(3) in rat osteoblast-like cells. 1204 5

The oxyntic mucosa is rich in ECL cells. They secrete histamine and chromogranin A-derived peptides, such as pancreastatin, in response to gastrin and pituitary adenylate cyclase-activating peptide (PACAP). Secretion is initiated by Ca2+ entry. While gastrin stimulates secretion by opening L-type and N-type Ca2+ channels, PACAP stimulates secretion by activating L-type and receptor-operated Ca2+ channels. Somatostatin, galanin and prostaglandin E2 (PGE2) inhibit gastrin- and PACAP-stimulated secretion from the ECL cells. In the present study, somatostatin and the PGE2 congener misoprostol inhibited gastrin- and PACAP-stimulated secretion 100%, while galanin inhibited at most 60-65%. Bay K 8644, a specific activator of L-type Ca2+ channels, stimulated ECL-cell secretion, an effect that was inhibited equally effectively by somatostatin, misoprostol and galanin (75-80% inhibition). Pretreatment with pertussis toxin, that inactivates inhibitory G-proteins, prevented all three agents from inhibiting stimulated secretion (regardless of the stimulus). Pretreatment with nifedipine (10 microM), an L-type Ca2+ channel blocker, reduced PACAP-evoked pancreastatin secretion by 50-60%, gastrin-evoked secretion by approximately 80% and abolished the response to Bay K 8644. The nifedipine-resistant response to PACAP was abolished by somatostatin and misoprostol but not by galanin. Gastrin and PACAP raised the intracellular Ca2+ concentration in a biphasic manner, believed to reflect mobilization of internal Ca2+ followed by Ca2+ entry. Somatostatin and misoprostol blocked Ca2+ entry (and histamine and pancreastatin secretion) but not mobilization of internal Ca2+. The present observations on isolated ECL cells suggest that Ca2+ entry rather than mobilization of internal Ca2+ triggers exocytosis, that gastrin and PACAP activate different (but over-lapping) Ca2+ channels, that somatostatin, misoprostol and galanin interact with inhibitory G-proteins to block Ca2+ entry via L-type Ca2+ channels, and that somatostatin and misoprostol (but not galanin) in addition block N-type and/or receptor-operated Ca2+ channels.
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PMID:Somatostatin, misoprostol and galanin inhibit gastrin- and PACAP-stimulated secretion of histamine and pancreastatin from ECL cells by blocking specific Ca2+ channels. 1593 92

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