Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Pituitary adenylate cyclase-activating polypeptide (PACAP), existing in two variants, PACAP-27 and PACAP-38, is found in the enteric nervous system and regulates function of the digestive system. However, the regulatory mechanism of PACAP on gastric acid secretion has not been well elucidated. We investigated the inhibitory action of PACAP-27 on acid secretion and its mechanism in isolated vascularly perfused rat stomach. PACAP-27 in four graded doses (5, 10, 20, and 50 microg/h) was vascularly infused to determine its effect on basal and pentagastrin (50 ng/h)-stimulated acid secretion. To study the inhibitory mechanism of PACAP-27 on acid secretion, a rabbit antisecretin serum, antisomatostatin serum, or indomethacin was administered. Concentrations of secretin, somatostatin, PGE(2), and histamine in portal venous effluent were measured by RIA. PACAP-27 dose-dependently inhibited both basal and pentagastrin-stimulated acid secretion. PACAP-27 at 10 microg/h significantly increased concentrations of secretin, somatostatin, and PGE(2) in basal or pentagastrin-stimulated state. The inhibitory effect of PACAP-27 on pentagastrin-stimulated acid secretion was reversed 33% by an antisecretin serum, 80.0% by an antisomatostatin serum, and 46.1% by indomethacin. The antisecretin serum partially reduced PACAP-27-induced local release of somatostatin and PGE(2). PACAP-27 at 10 microg/h elevated histamine level in portal venous effluent, which was further increased by antisomatostatin serum. However, antisomatostatin serum did not significantly increase acid secretion. It is concluded that PACAP-27 inhibits both basal and pentagastrin-stimulated gastric acid secretion. The effect of PACAP-27 is mediated by local release of secretin, somatostatin, and PGE(2) in isolated perfused rat stomach. The increase in somatostatin and PGE(2) levels in portal venous effluent is, in part, attributable to local action of the endogenous secretin.
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PMID:Inhibition of gastric acid secretion in rat stomach by PACAP is mediated by secretin, somatostatin, and PGE(2). 1064 70

ECL cells are endocrine/paracrine cells in the oxyntic mucosa. They produce, store and secrete histamine and chromogranin A-derived peptides such as pancreastatin. The regulation of ECL-cell secretion has been studied by several groups using purified ECL cells, isolated from rat stomachs. Reports from different laboratories often disagree. The purpose of the present study was to re-evaluate the discrepancies by studying histamine (or pancreastatin) secretion from standardized preparations of pure, well-functioning ECL cells. Cells from rat oxyntic mucosa were dispersed by pronase digestion, purified by repeated counter-flow elutriation and subjected to density gradient centrifugation. The final preparation consisted of more than 90% ECL cells (verified by histamine and/or histidine decarboxylase immunocytochemistry). They were maintained in primary culture for 48 h before they were exposed to candidate stimulants and inhibitors for 30 min after which the medium was collected for determination of mobilized histamine (or pancreastatin). Gastrin-17 and sulphated cholecystokinin octapeptide (CCK-8s) raised histamine secretion 4-fold, the EC(50) for both peptides being around 100 pM. The neuropeptide pituitary adenylate cyclase activating peptide (PACAP-27) (5-fold increase) and the related neuropeptides vasoactive intestinal peptide (VIP) and peptide histidine isoleucine (PHI) (3-fold increase) mobilized histamine with similar potency (EC(50) ranging from 80 to 140 pM). Adrenaline, isoprenaline and terbutaline stimulated secretion by activating a beta2 receptor subtype, while acetylcholine and carbachol were without effect. Secretion experiments were invariably run in parallel with a gastrin standard curve. Somatostatin, prostaglandin E2 (PGE2) and the PGE1 congener misoprostol inhibited PACAP- and gastrin-stimulated secretion by more than 90%, with IC(50) values ranging from 90-720 (somatostatin) to 40-200 (misoprostol) pM. The neuropeptide galanin inhibited secretion by 60-70% with a potency similar to that of somatostatin. Proposed inhibitors such as peptide YY, neuropeptide Y and the cytokines interleukin 1-beta and tumor necrosis factor alpha induced at best a moderate inhibition of gastrin- or PACAP-stimulated secretion at high concentrations, while calcitonin gene-related peptide, pancreatic polypeptide and histamine itself were without effect. Inhibition of gastrin- or PACAP-stimulated secretion was routinely compared to a somatostatin standard curve. In conclusion, gastrin, PACAP, VIP/PHI and adrenaline stimulated secretion. Somatostatin and PGE2 were powerful inhibitors of both gastrin- and PACAP-stimulated secretion; although equally potent, galanin was less effective than somatostatin and PGE2.
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PMID:Neurohormonal regulation of secretion from isolated rat stomach ECL cells: a critical reappraisal. 1116 53

Angiogenesis, the formation of a new blood supply, is an essential step in tumorigenesis. Although vascular endothelial growth factor (VEGF) is known to be a very potent angiogenic factor in most solid tumors, little is known about its production and regulation in pituitary adenomas. We have investigated basal and stimulated VEGF production by rodent pituitary tumor cells (mouse corticotrope AtT20, rat lactosomatotrope GH3, mouse gonadotrope alpha T3-1 and mouse folliculostellate TtT/GF cells), and by hormone-inactive (27), corticotrope (9), lactotrope (3) and somatotrope (21) human pituitary adenoma cell cultures. All 4 pituitary cell lines secreted VEGF, which in the case of AtT20, GH3 and TtT/GF cells was inhibited by approximately 50% by dexamethasone. TtT/GF cells were the most responsive to the different stimuli used since basal values were augmented by pituitary adenylate cyclase activating polypeptide-38 (PACAP-38), interleukin-6 (IL-6), transforming growth factor-alpha (TGF-alpha), IGF-I and the somatostatin analogue ocreotide. However, in GH3, AtT20 and alpha T3-1 cells, basal VEGF levels where not enhanced with any of the stimuli tested. The majority of the human adenomas tested (92%) basally secreted measurable VEGF which was inhibited by dexamethasone in most cases (84%). VEGF levels were increased in hormone inactive adenomas, somatotrope tumors and prolactinomas by TGF-alpha, PACAP-38, and 17 beta-estradiol, respectively. In conclusion, pituitary tumor cells are capable of producing VEGF which may be involved in tumoral angiogenesis. Our results concerning the suppression of VEGF by dexamethasone suggest that glucocorticoids may have anti-angiogenic properties and therefore therapeutic relevance for the treatment of pituitary adenomas.
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PMID:Vascular endothelial growth factor production and regulation in rodent and human pituitary tumor cells in vitro. 1147 17

A possible cross-competition between vasoactive intestinal peptide (VIP) and somatostatin (somatotropin release inhibiting factor; SRIF) and their respective receptors, was investigated at native or recombinant SRIF and VIP/pituitary adenylate cyclase-activating polypeptide (PACAP) receptors. The activity of VIP was examined in radioligand binding assays at mouse sst(1-5), rat sst(1-2) and human sst(1-5) receptors; or at human tumours preferentially expressing each of the five SRIF receptors. Moreover, SRIF was investigated at human tumoral tissues known to exclusively express specific VIP/PACAP receptor(s). VIP had no significant effect on any of the radioligand binding sites of the SRIF receptor family of rat, mouse or human origin tested. Conversely, SRIF did not interfere with the human VIP/PACAP binding sites tested. Taken together, the results cast reservation on the claimed cross-competition between VIP and SRIF at, specifically human sst(3) receptors, or any of the cloned SRIF or VIP/PACAP receptors recognised to date.
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PMID:Lack of evidence for cross-competition between vasoactive intestinal peptide and somatostatin at their respective receptors. 1152 40

Information about the expression of neuropeptide receptors is limited in human peripheral tissues, such as the gastrointestinal tract, as compared to the brain. A detailed evaluation of binding sites for gastrin-releasing peptide (GRP), neuropeptide Y, vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating polypeptide (PACAP), gastrin/cholecystokinin, neurotensin, substance P and somatostatin was therefore undertaken in human colon using in vitro receptor autoradiography and subtype characterization with receptor-selective ligands. GRP receptors, Y2 receptors, PACAP type1-receptors, cholecystokinin-A receptors, neurotensinl and sst2 receptors were abundantly expressed in the myenteric plexus. Y2, neurotensinl and sst2 receptors were also strongly expressed in the submucosal plexus. Furthermore, expression of GRP receptors, neurokinin (NK)1 receptors, VIP type2-receptors and sst2 receptors was found in the mucosa-directed margin of the circular smooth muscle where the interstitial cells of Cajal are located. A variable and complementary expression of GRP receptors, VIP/PACAP receptors, Y2 neurotensinl, NK1 and somatostatin receptors was found in the circular and longitudinal smooth muscle. NK1 and Y1 receptors were often detected in arteries and veins, while VIP/PACAP and sst2 receptors were found in lymphoid follicles. Y2, VIP type, and sst2 receptors were present in the colonic mucosa. Y2 was strongly expressed in the muscularis mucosae. This study shows that neuropeptide receptors are expressed in high amounts and in highly specific patterns in distinct targets in the human colon, suggesting a major physiological role for these peptides. The data represent the molecular basis to investigate the regulation by neuropeptides of colonic functions and to develop neuropeptide drugs aimed at interacting with these receptors in colonic diseases, such as Hirschsprung's and Crohn's diseases.
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PMID:Localization and characterization of neuropeptide receptors in human colon. 1168 16

In mammals, growth hormone (GH) is under a dual hypothalamic control exerted by growth hormone-releasing hormone (GHRH) and somatostatin (SRIH). We investigated GH release in a pleuronectiform teleost, the turbot (Psetta maxima), using a serum-free primary culture of dispersed pituitary cells. Cells released GH for up to 12 days in culture, indicating that turbot somatotropes do not require releasing hormone for their regulation. SRIH dose-dependently inhibited GH release up to a maximal inhibitory effect of 95%. None of the potential stimulators tested induced any change in basal GH release. Also, neither forskolin, an activator of adenylate cyclase, nor phorbol ester (TPA), an activator of protein kinase C, were able to modify GH release, suggesting that spontaneous basal release already represents the maximal secretory capacity of turbot somatotropes. In contrast, forskolin and TPA were able to increase GH release in the presence of SRIH. In this condition (coincubation with SRIH), pituitary adenylate cyclase-activating polypeptide (PACAP) stimulated GH release, whereas none of the other neuropeptides tested (GHRHs; sea bream or salmon or chicken II GnRHs; TRH; CRH) had any significant effect. These data indicate that inhibitory control by SRIH may be the basic control of GH production in teleosts and lower vertebrates, while PACAP may represent the ancestral growth hormone-releasing factor in teleosts, a role taken over in higher vertebrates by GHRH.
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PMID:Pituitary growth hormone secretion in the turbot, a phylogenetically recent teleost, is regulated by a species-specific pattern of neuropeptides. 1175 94

Reptiles, including the Burmese python, Python molurus bivittatus, that feed at infrequent intervals show a prominent increase in gastrointestinal mass, metabolism and brush border transport rates after feeding. Current knowledge and theories around these phenomena, as well as studies on the innervation of the reptilian gut, are summarised in this review. Little is known about the putative changes in the nervous and humoral control systems of the gut, and it is not known whether feeding affects innervation and motility of the stomach and intestine. Using immunohistochemistry, we have investigated possible up/down regulation of several neurotransmitters in specimens that had been fasted for a minimum of 3 weeks and specimens that had ingested a large meal 2 days before the experiments were conducted. There were no major changes in the innervation by nerves containing calcitonin gene-related peptide (CGRP), galanin, nitric oxide synthase (NOS), pituitary adenylate cyclase-activating polypeptide (PACAP), somatostatin (SOM), substance P/neurokinin A (SP/NKA), or vasoactive intestinal polypeptide (VIP)-like immunoreactivity. Nor did we find any differences in the effect of substance P (stomach and intestine), galanin (intestine), or bradykinin (intestine) on motility in strip preparations from the gut wall. A significant increase in dry weight of the intestine was obtained 48 h after feeding. We conclude that although there are considerable changes in gut thickness and absorptive properties after feeding, the smooth muscle and its control appear little affected.
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PMID:Effects of digestive status on the reptilian gut. 1244 9

Atrial natriuretic peptide (ANP) released from enterochromaffin cells helps regulate antral somatostatin secretion, but the mechanisms regulating ANP secretion are not known. We superfused rat antral segments with selective neural agonists/antagonists to identify the neural pathways regulating ANP secretion. The nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium (DMPP) stimulated ANP secretion; the effect was abolished by hexamethonium but doubled by atropine. Atropine's effect implied that DMPP activated concomitantly cholinergic neurons that inhibit and noncholinergic neurons that stimulate ANP secretion, the latter effect predominating. Methacholine inhibited ANP secretion. Neither bombesin nor vasoactive intestinal polypeptide stimulated ANP secretion, whereas pituitary adenylate cyclase-activating polypeptide (PACAP)-27, PACAP-38, and maxadilan [PACAP type 1 (PAC1) agonist] each stimulated ANP secretion. The PAC1 antagonist M65 1) abolished PACAP-27/38-stimulated ANP secretion; 2) inhibited basal ANP secretion by 28 +/- 5%, implying that endogenous PACAP stimulates ANP secretion; and 3) converted the ANP response to DMPP from 109 +/- 21% above to 40 +/- 5% below basal, unmasking the cholinergic component and indicating that DMPP activated PACAP neurons that stimulate ANP secretion. Combined atropine and M65 restored DMPP-stimulated ANP secretion to basal levels. ANP secretion in the antrum is thus regulated by intramural cholinergic and PACAP neurons; cholinergic neurons inhibit and PACAP neurons stimulate ANP secretion.
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PMID:Regulation of atrial natriuretic peptide secretion by cholinergic and PACAP neurons of the gastric antrum. 1248 35

Secretin is released from upper small intestinal mucosa to drive pancreatic secretion of fluid and bicarbonate and inhibit gastric acid secretion. Recently, we found that, in isolated, vascularly perfused rat stomach model, the inhibition of acid secretion by pituitary adenylate cyclase activating polypeptide (PACAP) was mediated in part via local release of secretin. However, the presence of secretin-producing cells and mRNA in gastric mucosa, particularly in oxyntic mucosa, has not been established. The present study was carried out to establish the presence of secretin cells by immunohistochemical and mRNA by biochemical methods in gastric mucosa. Secretin cells were identified in antral mucosa (27.8 +/- 2.0 cells/mm(2)) and corpus (4.7 +/- 0.5 cells/mm(2)). They were distinguishable, through double immunostaining, from gastrin and somatostatin cells in the antrum and from somatostatin cells in the corpus. The results of reverse transcription (RT)-PCR and Southern blot indicated that a secretin gene transcript of 454 bp was present in the mRNA extracts of both antral and corpus mucosae. The results indicated that secretin mRNA is present in gastric mucosa. In conclusion, secretin-producing cells and mRNA are present in gastric mucosa and the locally released secretin may exert a paracrine effect to inhibit acid secretion.
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PMID:Evidence on the presence of secretin cells in the gastric antral and oxyntic mucosa. 1260 67


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