UMLS:C0043167 - FACTA Search

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Query: UMLS:C0043167 (pertussis)
19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Muscarine and somatostatin enhance an inward rectifier K+ conductance in the AtT-20 pituitary cell line. Both effects are abolished by pertussis toxin (PTX). To determine which PTX-sensitive G protein mediates these agonist effects, we made cDNAs encoding mutant PTX-insensitive Gi alpha subtypes, in which the cysteine residue fourth from the C terminus was replaced with serine. The mutated cDNA was transfected into AtT-20 cells, resulting in stable cell lines overexpressing a Gi alpha subtype. As controls, wild-type Gi alpha cDNA was transfected into AtT-20 cells. The agonist-induced increase of the inward rectifier K+ conductance in the transfectants was examined with the whole-cell clamp method. Only in the cell lines into which the mutated (PTX-insensitive) Gi2 alpha cDNA was transfected, did the muscarine response become PTX-insensitive, suggesting that Gi2 couples to the muscarinic receptor and enhances the activity of the inward rectifier K+ channel. However, PTX-insensitive somatostatin responses were not obtained in any of the cell lines transfected with a mutated Gi alpha cDNA, suggesting either that none of the Gi subtypes is a transducer for the somatostatin effect or that the mutation prevents the coupling of the Gi alpha to the somatostatin receptor.
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PMID:G protein specificity of the muscarine-induced increase in an inward rectifier potassium current in AtT-20 cells. 912 37

We studied the activation of the human somatostatin5 receptor recombinantly expressed in CHO-K1 cells by using some newly available agonists and antagonists. Somatostatin-28 bound to this receptor with a higher affinity than somatostatin-14 and was more potent in increasing [35S]guanosine-5'-O-(3-thio)triphosphate ([35S]GTPgammaS) binding. Somatostatin-14-induced [35S]GTPgammaS binding to membranes from this cell line was decreased in a concentration-related manner by increasing concentrations of GDP and sodium chloride. At 50 mM (low) sodium, agonist EC50 values for stimulating [35S]GTPgammaS binding were lower than those at 150 mM (high) sodium and were closer to their respective affinity estimates (dissociation equilibrium constants) for binding to the receptor in the absence of sodium. Both agonist binding to the high affinity state of the receptor and agonist-induced [35S]GTPgammaS binding were abolished by pertussis toxin pretreatment. The putative somatostatin5 receptor-selective ligand L-362,855, unlike somatostatin-14 and somatostatin-28, showed differential intrinsic activity for stimulation of [35S]GTPgammaS binding, behaving as a partial agonist in high sodium and a full agonist in low sodium. In contrast, BIM-23056 did not behave as an agonist under any conditions studied but was able to antagonize somatostatin-14-induced [35S]GTPgammaS binding. We conclude that measurement of [35S]GTPgammaS binding mediated by somatostatin receptor activation in the presence of different concentrations of sodium chloride provides a useful functional assay for assessing the relative agonist efficacies of novel ligands identified from radioligand binding studies.
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PMID:Somatostatin5 receptor-mediated [35S]guanosine-5'-O-(3-thio)triphosphate binding: agonist potencies and the influence of sodium chloride on intrinsic activity. 918 73

Interleukin 6 is a pleiotropic cytokine produced in the central nervous system (CNS) that has been involved in both direct neurotrophic activities and in the regulation of the production of acute phase proteins both at peripheral and central levels. In rat cortical type I astrocytes, interleukin 6 release is under the control of cAMP-protein kinase A and calcium-phospholipids-protein kinase C systems. Somatostatin is a neuropeptide, acting as a neurotransmitter, highly concentrated within the CNS, where it has been involved in the modulation of learning and memory processes. The aim of this study was to characterize the effects of somatostatin on the release of interleukin 6 from rat cortical type I astrocytes and the intracellular mechanisms involved in this activity. Our results show that somatostatin, in a concentration-dependent manner, inhibited basal and forskolin-stimulated interleukin 6 release from rat cortical type I astrocytes in culture. The EC50 of the inhibitory action was calculated to be approximately 10 nM. Furthermore, this effect of somatostatin was completely abolished by pretreating cortical astrocytes with pertussis toxin that, uncoupling, by ADP-rybosylating, the inhibitory GTP-binding protein from the receptors, prevents the activation of the intracellular effectors such as the adenylyl cyclase enzyme. To identify the intracellular mechanism mediating the effects of somatostatin on the interleukin 6 release, we evaluated the peptide modulation of basal and stimulated intracellular accumulation of cAMP. In our experimental conditions somatostatin significantly inhibited both basal and forskolin-stimulated cAMP accumulation. Conversely, somatostatin did not affect the increase of interleukin 6 release induced by dibutyryl-cAMP, a nonhydrolizable cAMP analog that, bypassing the effects of somatostatin on adenylyl cyclase activity, directly activated protein kinase A. These observations support the hypothesis that somatostatin inhibitory activity on interleukin 6 release is mediated by its effects on cAMP production. Somatostatin analog SMS 201-995 did not affect interleukin 6 production either in basal or stimulated conditions. Since, SMS 201-995 was reported to bind with high affinity only to somatostatin receptors type 2, 3 and 5, the lack of effect of this compound on interleukin 6 release suggests that the inhibitory action of somatostatin could be mediated by the activation of either type 1 or type 4 somatostatin receptors. In conclusion, our data demonstrate that the release of interleukin 6 from rat cortical type I astrocytes is inhibited by somatostatin through the activation of a somatostatin receptor coupled to the inhibition of adenylyl cyclase via a G-protein sensitive to pertussis toxin.
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PMID:Somatostatin inhibits interleukin 6 release from rat cortical type I astrocytes via the inhibition of adenylyl cyclase. 919 70

The purpose of these experiments was to demonstrate the presence of somatostatin receptors on the nonpigmented epithelial cells of the rabbit ciliary body and their link with intracellular Ca2+ homeostasis. Freshly excised rabbit ciliary processes and nonpigmented cell layer, explants were loaded with the fluorescent dye fura-2, and free-Ca2+ concentration ([Ca2+]i) in the nonpigmented cells was measured with fluorescence ratio imaging. The cells were continuously perfused, and drugs were added to the perfusate. Somatostatin-14 (SS14, 0.1-1.0 microM) or acetylcholine (ACh, 10 microM) applied alone produced small increases in [Ca2+]i. However, SS14 (0.1 microM) in combination with ACh (10 microM) induced a massive increase in [Ca2+]i (25.7 +/- 3.3 times the baseline level, n = 28). The dose-response curve for SS14 (in the presence of 10 microM ACh) was sigmoidal with an EC50 of 3.9 nM and Hill coefficient of 2.5, indicating the requirement for multiple SS receptor activation. Somatostatin-28 could mimic the effect of SS14, although a much higher concentration was required. Shifting the SS14 dose-response curve to the right by about two-orders of magnitude resulted in a fit to the SS28 data. The response to ACh + SS14 could not be blocked by the alpha 2-adrenergic blocker yohimbine (Yoh, 10 microM) or the A1-specific adenosinergic antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 1 microM). Incubation of the tissue with pertussis toxin (PTx, 1 microgram ml-1) did not alter the response to ACh alone but eliminated the synergistic effect of somatostatin. We conclude that nonpigmented epithelial cells of the rabbit ciliary body possess a novel somatostatin receptor whose activation can synergistically potentiate the rise in [Ca2+]i produced by ACh. This potentiation appears to occur via a pertussis-toxin-sensitive pathway, perhaps through Gi.
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PMID:Synergistic rise in Ca2+ produced by somatostatin and acetylcholine in ciliary body epithelial cells. 922 81

To elucidate the signaling events mediated by specific somatostatin receptor (SSTR) subtypes, we expressed SSTR1 and SSTR2 individually in rat pituitary GH12C1 and F4C1 cells, which lack endogenous somatostatin receptors. In transfected GH12C1 cells, both SSTR1 and SSTR2 coupled to inhibition of Ca2+ influx and hyperpolarization of membrane potential via a pertussis toxin (PTx)-sensitive mechanism. These effects reflected modulation of ion channel activities which are important for regulation of hormone secretion. Somatostatin analogs MK678 and CH275 acted as subtype selective agonists as expected. In transfected F4C1 cells, both SSTR1 and SSTR2 mediated somatostatin-induced inhibition of adenylyl cyclase via a PTx-sensitive pathway. In addition, activation of SSTR2 in F4C1 cells, but not SSTR1, stimulated phospholipase C (PLC) activity and an increase in [Ca2+]i due to release of Ca2+ from intracellular stores. Unlike adenylyl cyclase inhibition, the PLC-mediated response was only partially sensitive to PTx. To determine the structural determinants in SSTR2 necessary for activation of PLC, we constructed chimeric receptors in which domains of SSTR2 were introduced into SSTR1. Chimeric receptors containing only the third intracellular loop, or all three intracellular loops from SSTR2, mediated inhibition of adenylyl cyclase, but failed to stimulate PLC activity as did wild-type SSTR2. Furthermore, the C-terminal tail of SSTR2 was not required for coupling to PLC. Thus, by expressing individual somatostatin receptor subtypes in pituitary cells, we have identified both overlapping and distinct signaling pathways for SSTR1 and SSTR2, and have shown that sequences other than simply the intracellular domains are required for SSTR2 to couple to the PLC signaling pathway.
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PMID:Both overlapping and distinct signaling pathways for somatostatin receptor subtypes SSTR1 and SSTR2 in pituitary cells. 922 36

We investigated cell proliferation modulated by cholecystokinin (CCK) and somatostatin analogue RC-160 in CHO cells bearing endogenous CCKA receptors and stably transfected by human subtype sst5 somatostatin receptor. CCK stimulated cell proliferation of CHO cells. This effect was suppressed by inhibitor of the soluble guanylate cyclase, LY 83583, the inhibitor of the cGMP dependent kinases, KT 5823, and the inhibitor of mitogen-activated protein (MAP) kinase kinase, PD 98059. CCK treatment induced an increase of intracellular cGMP concentrations, but concomitant addition of LY 83583 virtually suppressed this increase. CCK also activated both phosphorylation and activity of p42-MAP kinase; these effects were inhibited by KT 5823. All the effects of CCK depended on a pertussis toxin-dependent G protein. Somatostatin analogue RC-160 inhibited CCK-induced stimulation of cell proliferation but it did not potentiate the suppressive effect of the inhibitors LY 83583 and KT 5823. RC-160 inhibited both CCK-induced intracellular cGMP formation as well as activation of p42-MAP kinase phosphorylation and activity. This inhibitory effect was observed at doses of RC-160 similar to those necessary to occupy the sst5 recombinant receptor and to inhibit CCK-induced cell proliferation. We conclude that, in CHO cells, the proliferation and the MAP kinase signaling cascade depend on a cGMP-dependent pathway. These effects are positively regulated by CCK and negatively influenced by RC-160, interacting through CCKA and sst5 receptors, respectively. These studies provide a characterization of the antiproliferative signal mediated by sst5 receptor.
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PMID:Characterization of the antiproliferative signal mediated by the somatostatin receptor subtype sst5. 925 84

Activation of the somatostatin receptor sst2, a member of the Gi protein-coupled receptor family, results in the stimulation of a protein-tyrosine phosphatase activity involved in the sst2-mediated growth inhibitory signal. Here, we report that SHP-1, a cytoplasmic protein-tyrosine phosphatase containing two Src homology 2 domains constitutively associated with sst2 as evidence by coprecipitation of SHP-1 protein with sst2, in Chinese hamster ovary cells coexpressing sst2 and SHP-1. Activation of sst2 by somatostatin resulted in a rapid dissociation of SHP-1 from sst2 accompanied by an increase of SHP-1 activity. SHP-1 was phosphorylated on tyrosine in control cells and somatostatin induced a rapid and transient dephosphorylation on tyrosine residues of the enzyme. Stimulation of SHP-1 activity by somatostatin was abolished by pertussis toxin pretreatment of cells. Gialpha3 was specifically immunoprecipitated by anti-sst2 and anti-SHP-1 antibodies, and somatostatin induced a rapid dissociation of Gialpha3 from sst2, suggesting that Gialpha3 may be involved in the sst2.SHP-1 complexes. Finally, somatostatin inhibited the proliferation of cells coexpressing sst2 and SHP-1, and this effect was suppressed in cells coexpressing sst2 and the catalytic inactive SHP-1 (C453S mutant). Our data identify SHP-1 as the tyrosine phosphatase associated with sst2 and demonstrate that this enzyme may be an initial key transducer of the antimitogenic signaling mediated by sst2.
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PMID:The tyrosine phosphatase SHP-1 associates with the sst2 somatostatin receptor and is an essential component of sst2-mediated inhibitory growth signaling. 930 5

The modulation of N-type voltage-gated calcium (Ca2+) channels by G protein-coupled receptors was investigated in sympathetic neurons of the male rat major pelvic ganglion (MPG) with the use of whole cell patch-clamp recording techniques from acutely dissociated neurons. By inhibiting calcineurin, a Ca2+/calmodulin-regulated protein phosphatase, the alpha2 noradrenergic and somatostatin receptor-induced inhibition of these N-type Ca2+ channels was greatly reduced. Both of these receptor pathways utilize a pertussis toxin-sensitive G protein (G(PTX)). The guanosine 5'-o-(3-thiotriphosphate) (GTPgammaS)-induced decrease in the amplitude and activation kinetics of Ca2+ currents, an effect that was similar to the activation of G(PTX)-coupled receptors, also was reduced by the inhibition of calcineurin. Calcineurin does not regulate the muscarinic receptor-induced inhibition of the N-type Ca2+ channels, a pathway that utilizes a different G protein in the MPG neurons. Thus calcineurin appears to selectively regulate the coupling between the G(PTX) and the Ca2+ channel.
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PMID:Calcineurin modulates G protein-mediated inhibition of N-type calcium channels in rat sympathetic neurons. 930 44

We compared internalization of three radioiodinated octreotide (OCT) somatostatin (SS) analogs-[125I-Tyr3]OCT, [DTPA degrees, 125I-Tyr3]OCT, and [DOTA degrees,125I-Tyr3]OCT-by somatostatin receptor (SSR)-positive mouse AtT20 pituitary tumor cells and human insulinoma cells. The three SS analogs were internalized in a specific, time-dependent manner. Internalization was significantly inhibited by pertussis toxin (100 microg/l) by 38%, 43%, and 31%, and by an inhibitor of receptor-mediated endocytosis (phenyl arsine oxide; 10 microM) by 98%, 94%, and 92%, respectively. Binding affinities of the three radioligands were comparable (0.2, 0.2, and 0.3 nM, respectively). However, [DOTA degrees,125I-Tyr3]OCT was internalized in a five-fold higher amount in comparison with the two other radioligands. A comparably high uptake of [DOTA degrees, 125I-Tyr3]OCT was found in SSR-positive organs (pituitary, pancreas, and adrenals) in vivo in rats (a ten-fold, five-fold, and eight-fold higher uptake 4 hr post injection, respectively, compared with the two other radioligands). This resulted in very high target-background ratios for [DOTA degrees,125I-Tyr3]OCT 4 hr post injection amounting to 274, 566, and 623 in the pituitary, adrenals, and pancreas, respectively. Both in vivo and in vitro there was a rapid dissociation of radioactivity from the SSR-positive cells. Main conclusions are that: 1) coupling of chelating groups like DTPA or DOTA to the SS analog [Tyr3]OCT does not prevent the internalization of OCT after binding to SSRs; 2) [DOTA degrees, 125I-Tyr3]OCT is internalized in a significantly higher amount by AtT20 and human insulinoma cells and in vivo in rats in SSR-positive organs, in comparison with [DTPA degrees,125I-Tyr3]OCT and [125I-Tyr3]OCT; and 3) the very high target-background ratios in vivo make radioiodinated [DOTA degrees,Tyr3]OCT a very suitable ligand for SSR-targeted radioguided surgery of SSR-positive human neuroendocrine tumors.
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PMID:Internalization of [DOTA degrees,125I-Tyr3]Octreotide by somatostatin receptor-positive cells in vitro and in vivo: implications for somatostatin receptor-targeted radio-guided surgery. 989 58

The inhibitory effect of the neuropeptide somatostatin on the expression of growth hormone was measured by quantitative polymerase chain reaction in the pituitary cell line AtT-20. We demonstrate that this effect is dependent on the internalization of somatostatin-receptor complexes and that it is totally independent from the peptide-induced inhibition of adenylate cyclase. Indeed, the inhibitory effect of the peptide on growth hormone mRNA levels was totally insensitive to pertussis toxin treatment but was totally abolished under conditions which block somatostatin receptor internalization. Comparative confocal microscopic imaging of fluorescent somatostatin sequestration and fluorescence immunolabeling of sst1, sst2A, and sst5 receptors suggests that sst2A is most probably responsible of the inhibitory effect of somatostatin on growth hormone expression.
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PMID:Receptor-mediated internalization is critical for the inhibition of the expression of growth hormone by somatostatin in the pituitary cell line AtT-20. 1038 39

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